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Chapter 4. Analgetics — Strong and Weak
Chapter 4, A n a l g e t i c s --- S t r o n g and Weak Louis S. H a r r i s and W i L L i a m L. Dewey U n i v e r s i t y of N o r t h C a r o l i n a , Chapel H i l l , N.C. I. I n t r o d u c t i o n
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The p a s t y e a r h a s been unique i n r e c e n t
t i m e s i n t h a t a s u b s t a n t i a l number of new a n a l g e s i c s have become a v a i l a b l e f o r g e n e r a l m e d i c a l u s e i n t h i s c o u n t r y . These incL ude t h e non -narc0 t i c pheno t h i a z i n e m e t ho t r imepr a z i n e , t h e
n a r c o t i c - a n t a g o n i s t a n a l g e s i c pentazocine, t h e mild a n a l g e s i c mefenamic a c i d , and t h e n e u r o L e p t a n a l g e s i c m i x t u r e of f e n t a n y l and d r o p e r i d o l . Although s y n t h e t i c work i n t h e a n a l g e s i c area h a s n o t been l a r g e , some i n t e r e s t i n g new compound classes have appeared which have b o t h p o t e n t i a l c l i n i c a l u s e f u l n e s s a n d t h e o r e t i c a L importance i n o u r s e a r c h f o r an u n d e r s t a n d i n g o f how a n a l g e s i c s act. 11. S t r o n g AnaLgesics
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A. Mor h i n e L i t t l e new i n t h e way of s y n t h e t i c work w a s p u b l i s h +--Ti e i n t is area. However, Rapoport and h i s groupLy2 have continued t h e i r e l e g a n t work on t h e b i o s y n t h e s i s o f t h e E a r l i e r B a t o n and h i s c o l l e a g u e s 3 and opium a l k a l o i d s . B a t t e r s b y and h i s a s s o c i a t e s ' had p u t f o r t h e v i d e n c e t h a t This r e t i c u l i n e ( I ) served as a p r e c u r s o r of t h e b a i n e (11). r o l e h a s now been f i r m l y e s t a b l i s h e d i n f r e s h budding p l a n t s
V
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and s e e d l i n g s exposed t o 14C02 f o r s h o r t p e r i o d s u t i l i z i n g gas chromatography w i t h s i m u l t a n e o u s mass and a c t i v i t y measurements f o r a n a l y s i s . The r o u t e t o morphine i s t h e s a m e i n s e e d l i n g s as i n mature p l a n t s and f o l l o w s t h e scheme: C02+reticuLine
+thebaine
+ codeine+morphine
The i n t i m a t e d e t a i l s of t h e c o n v e r s i o n of t h e b a i n e t o c o d e i n e h a s a l s o been worked out2y5. Thebaine (11) i s demethylated t o a p o s t u l a t e d t a u t o m e r i c m i x t u r e of neopinone (111) and c o d e i Although t h e none ( I V ) followed by r e d u c t i o n t o c o d e i n e ( V ) . opium poppy i s c a p a b l e o f d e m e t h y l a t i n g c o d e i n e methyl e t h e r , t h e p l a n t a p p a r e n t l y d o e s n o t u s e t h i s r o u t e and t h e r e p o r t e d i s o l a t i o n of t h i s compound i s a t t r i b u t e d t o t h e r e d u t i o n o f t h e b a i n e i n t h e i s o l a t i o n and p u r i f i c a t i o n p r o c e s s e s
8.
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B. O r i p a v i n e Analogs - A c l a s s i c series of p a p e r s by Bentley and h i s c o l l e a g u e s 7 d e s c r i b e t h e s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s of a w i d e v a r i e t y of s t r u c t u r e s d e r i v e d from D i e L s - A l d e r a d d u c t s of t h e b a i n e . Among t h i s group are found some of t h e most p o t e n t a n a l g e s i c s known. Particular attent i o n should be d i r e c t e d toward t h e f i n e a p p l i c a t i o n of n u c l e a r magnetic r e s o n a n c e s p e c t r o s c o p y , by Fulmor and h i s a s s o c i a t e s g t o e l u c i d a t e t h e s t e r e o c h e m i c a l c o n f i g u r a t i o n s of t h e s e i n teres t i n g compound s . The pharmacology of one of t h e more p o t e n t morphine-Like members of t h i s s e r i e s , e t o r p h i n e (M-99, V I ) , h a s r e c e n t l been more e x t e n s i v e l y d e s c r i b e d by BLane and h i s groupg, L8*ll. Depending on t h e t e s t system t h i s compound proved t o be L , O O O -
A: R=R'=C 2H5 B: R=G, R'=CH HO
R
VII
3
R'=CH C: R=C H 3 7' 3
80,000 t i m e s more p o t e n t t h a n morphine. It w a s q u a l i t a t i v e l y s i m i l a r t o morphine w i t h t h e e x c e p t i o n t h a t Low d o s e s o f e t o r p h i n e d i d n o t produce e x c i t e m e n t o r emesis i n dogsg, The d i s t r i b u t i o n of e t o r p h i n e i n t h e p r e g n a n t r a t w a s compared w i t h t h a t of dihydromorphineLO. E t o r p h i n e i s found t o e n t e r and c o n c e n t r a t e more r a p i d l y t h a n dihydromorphine i n t h e b r a i n s of b o t h t h e mothers and t h e f o e t u s e s . Up t o twenty minutes a f t e r i n t r a m u s c u l a r a d m i n i s t r a t i o n t h e c o n c e n t r a t i o n This of e t o r p h i n e w a s h i g h e r i n t h e b r a i n t h a n i n t h e blood. The may e x p l a i n , i n p a r t , t h e h i g h p o t e n c y of t h i s compound. r a p i d p a s s a g e of e t o r p h i n e a c r o s s t h e pLacentaL b a r r i e r and i t s accumulation i n t h e fetaL b r a i n may a l s o e x p l a i n t h e neon a t a l m o r t a l i t y observed a f t e r Large d o s e s of t h i s d r u g , a phenomenon n o t observed w i t h morphine. Evidence has a l s o been p r e s e n t e d t o show t h a t if one a v o i d s t h e s h a r p a b s o r p t i o n peak of e t o r p h i n e , by g i v i n g t h e d r u g s u b l i n g u a l l y , t h e f e t a l r e s p i r a t o r y d e p r e s s i o n and L e t h a l i t y are much LessLL.
C. Benzomorphans - O f i n t e r e s t i s t h e c o n t i n u e d f i n d i n g i n t h e s e compounds of a s t e r e o s p e c i f i c s e p a r a t i o n between a n a l g e s i c a c t i v i t y , as measured by t h e h o t - p l a t e t e c h n i q u e , and ? $ d i c t i o n L i a b i l i t y as assessed i n t h e monkey. May and Eddy had e a r l i e r report'ed t h e r e s o l u t i o n of c i s - 5 , g - d i e t h y l 2 ' -hydroxy-2-methyl-6,7-benzomorphan ( V I I A ) . The ( + ) - i s o m e r had weak a n a l g e s i c a c t i v i t y b u t a h i g h p h y s i c a l dependence c a p a c i t y (PDC). The ( - ) - i s o m e r had h i g h a n a l g e s i c a c t i v i t y y e t proved t o be n a l o r p h i n e - l i k e ( i . e . p r e c i p i t a t e d a b s t i nence) i n a d d i c t e d monkeys. Similar findings w e r e obtained More r e c e n t l y t h e 5w i t h t h e 5-phenyL compound V I I B L 3 a . propyl-9-methyl d e r i v a t i v e V I I C w a s a l s o resoLved and t e s t e d (.
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CNSAgents
Again, t h e (+) -isomer i s a considerabLy Less p o t e n t a n a l g e s i c than t h e (-) -isomer y e t has a h i g h PDC. (-)-isomer beThe (-)-isomer haves Like n a l o r p h i n e i n a d d i c t e d monkeys of V I I A i n t h e t r a n s -conf i g u r a t ion h a s a l s o befgbprepared. It i s a p o t e n t m e s i c w i t h L i t t l e o r no PDC It had no antagonistic activity. Primary a d d i c t i o n s t u d i e s i n monkeys w e r e carried o u t w i t h both (-1 - c i s - and ( - ) - t r a n s - V I I A . The (-)-cis-compound produced few m G h i n e - l i k e a b s t i n e n c e s i g n s on a b r u p t w i t h drawal a f t e r prolonged a d m i n i s t r a t i o n . The ( - ) -trans-compound produced a t y p i c a l morphine-Like a b s t i n e n c e . D. Miscellaneous - Davis and h i s c o l l e a g u e s L 4 r e p o r t e d a series of a m i t r y p t y l i n e analogs c o n t a i n i n g t h e normeperidine group as t h e b a s i c n i t r o g e n . S e v e r a l o f t h e s e had p o t e n t a n a l g e s i c p r o p e r t i e s , The g e n e r a l s t r u c t u r e i s shown as V I I I . Optimum a c t i v i t y w a s achieved when Y= =CHCH2- and Z i s t h e 0 A: R=CH2-@-OC2H5 CH3CH2!6-@ (NOq) m B : R= S-0-OC2H5
.
.
7
9
VIII
-N3pl Z
,
IX
I
X
dCH2 12N (C2H5)
(332CH2Q(
S u b s t i t u t i n g a phenothiazine o r reversed e s t e r -OCOC2H5. benzhydryl f o r t h e d lbenzocycloheptene s y s t e m Lowered a c t i v i t y . A l s o of i n t e r e s t i n t h e meperidine f i e l d i s t h e r e p o r t L5 t h a t meperid he-N-oxide i s e q u i p o t e n t w i t h meperidine w i t h a Longer d u r a t i o n of a c t i o n . Fentanyl (1x1 t h e meperidine anakg i n t h e n e u r o l e p t a n a l g e s i c mixture Innovar, w a s t e s t e d f o r a n a l g e s i a c t i v i t y i n man and found t o be 50x more p o t e n t than morphine f 6
.
A number of r e p o r t s of new s q t h es i n t h e benzimidaz o l e series (XA) have been r e p o r t e d 7-f4. A s would be exp e c t e d , a c t i v e compounds w e r e o b t a i n e d . The nec s ' t y o f t h e 5 - n i t r o group f o r m a x i m a l a c t i v i t y w a s confirmed f.'f,t8. Subs t i t u t i o n of a 2-thiophenyl (XB) a l s o Lowered a c t i v i t y L g .
A series of L6-(3-amino-L7~-20-dih droxypregnanes having a n a l g e s i c a c t i v i t y have been described28. A s i m i l a r compound,
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Harris, D e w e y
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X I , w a s s t u d i e d f o r addktion L i a b i l i t y i n m 0 n k e y s l 3 ~ . N o Solus u p p r e s s i o n of a b s t i n e n c e w a s noted up t o L 5 mg/kg. b i l i t y prevented h i g h e r doses b u t s i g n s of m i x e d s t i m u l a t i o n and s e d a t i o n w e r e observed, An a l k a l o i d of t h e voacanga
0
XI11
XIV
s e r i e s , spnopharyngine (XII) , w a s a l s o shown t o have a n a l g e s i c activity The a n a l g e s i a observed w a s unaccompanied by motor i n c o o r d i n a t i o n and w a s n o t antagonized by n a l o r p h i n e . The L , 3 - t h i a z i n e X I 1 1 h a s been r e q q r t e d t o have s t r o n g a n a l g e s i c p r o p e r t i e s i n animals and man The compound has a h i g h s e d a t i v e and a n t i h y p e r t e n s i v e component and a c t s Like morphine on t h e e l e c t r i c a l l y s t i m u l a t e d g u t . Also of i n t e r e s t are t h e amphetamine d e r i v a t i v e aletarnine (XIV) and t h e pyrr o l i d i n e d e r i v a t i v e , p r o f a d o l (XV). Both of t h e s e compounds have been r e p o r t e d t o have a n a l g e s i c p r o p e r t i e s i n animals and man a l t h o u g h aletamine w a s q u i t e weak. P r o f a d o l i s c u r r e n t L y b e i n g e v a l u a t e d a t Lexington f o r a d d i c t i o n L i a b i l i t y , A L e t a mine had no PDC i n a d d i c t e d monkeys and i n pr’mary a d d i c t i o n s t u d i e s no morphine-like a b s t i n e n c e w a s seenL3a. E. Biochemical and Pharmacological C o n s i d e r a t i o n s - A number of p a p e r s appeared which i m p l i c a t e d t h e c e n t r a l a d r e n e r g i c system w i t h a n a l g e s i a . V e r r i and co-workers23 reported t h a t premedication w i t h r e s e r p i n e or a - m e t h y l t y r o s i n e antagonized t h e a n a l g e s i c a c t i o n of morphine i n mice. The c e n t r a l s t i m u l a t i n g a c t i o n of m3f;phine w a s r e d u c e d by p r e treatment a-methyltyrosine On t h e o t h e r hand, Ross and Ashford reported t h a t pretreatment with res erp in e in h i b i t e d t h e a n a l g e s i c a c t i o n of morphine i n t h e t a i l cLip t e s t and p o t e n t i a t e d morphine’s a c t i o n i n t h e h o t p l a t e t e s t . a-Methyldopa p r e t r e a t m e n t prevented t h e i n h i b i t o r y e f f e c t o f r e s e r p i n e on t h e taiL c l i p t e s t and showed a n a l g e s i c a c t i o n i t s e l f i n t h e h o t p l a t e t e s t , C o n t r e r a s and h i s co-workers26 demonstrated t h e a n a l g e s i c a c t i v i t y o f methyldopa and ergonov i n e , and t h a t t o l a z o l i n e can a n t a g o n i z e t h e a n a l g e s i a p r o duced by many n a r c o t i c a n a l g e s i c s . T h i s antagonism appeared t o be c o m p e t i t i v e i n t h a t t h e t o l a z o l i n e block c o u l d be o v e r come by h i h e r doses of meperidine and phenazocine. Takagi and NakamaS7 found a r e d u c t i o n i n mouse b r a i n n o r e p i n e p h r i n e and dopamine foLlowing t h e combined i n j e c t i o n of morphine and nalorphine. Nalorphine a l o n e had no e f f e c t on t h e b r a i n cont e n t of t h e s e amines. Morphine and r e l a t e d a g e n t s have been shown t o cause a release of 5-hydroxytryptamine (5-HT) i n t h e s m a l l i n t e s t i n e
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of t h e d ~ tgh a t corresponds t o t h e i n c r e a s e d i n t e s t i n a l t o n e observed , F u r t h e r e v i d e n c e f o r t h e r o l e of 5-HT i n t h e g a s t r o i n t e s t i n a l e f f e c t s of morphine w e r e demonstrated when it w a s observed t h a t methysergide, a p o t e n t i n h i b i t o r of 5-HT, antagonized t h e f f e c t s of morphine on g a s t r o i n t e s t i n a l prop u l s i o n i n m i c e 29
.
In m i c e 8-azaguanine, an i n h i b i t o r f r o t e i n s y n t h e s i s , antagonized t h e development of t 0 l e r a n c e 3 ~Sp. Morphine i n j e c t i o n s i n h i b i t e d t h e i n c o r p o r a t i o n of14C Leucine i n t o b r a i n p r o t e i n s . T h i s e f f e c t of morphine could be blocked by keeping t h e r a t s a t an ambient temperaty5e of 30° and by t h e s i m u l taneous i n j e c t i o n of n a l o r p h i n e The r e l a t i o n s h i p of morphine's action t o protein synthesis o r nucleic acids i s s t i l l not clear. Mul633 r e p o r t e d t h a t P 32 uptake i n t o c o r t i c a l s l i c e s w a s s t i m u l a t e d by t h e subcutaneous a d m i n i s t r a t i o n o f morphine t o n o n - t o l e r a n t guinea p i g s , Chronic morphine t r e a t m e n t i n h i b i t s t h i s i n c r e a s e d phospholid metabolism. The uptake of P 32 i n t o p o l y p h o s p h o i n o s i t i d e s w a s markedly enhanced by c o r t i c a l s l i c e s from a b s t i n e n t g u i n e a p i g s i n t h e p r e s e n c e of morphine, E s t l e r 3 4 c o r r e l a t e d e x c i t e m e n t produced by morphine i n mice w i t h a decrease i n b r a i n glycogen, and an i n c r e a s e i n b r a i n glycogen o f rats s e d a t e d by an i n j e c t i o n of morphine. R a t i o s o f phosphorylase-a t o t o t a l phosphorylase w a s d i r e c t l y reLated t o changes i n glycogen. A s i n o t h e r s t u d i e s of t h i s t y p e i t i s d i f f i c u l t t o a s c e r t a i n whether t h e biochemical changes w e r e t h e c a u s e o r t h e r e s u l t of t h e observed pharmac o l o g i c a l response, A number o f s t u d i e s c o n c e r n i n g t h e m e t a b o l i c f a t e of morphine and t s analogs have been r e p o r t e d . Thus, C a s t r o and G i L L e t t e 3 & s t u d i e d t h e metabolism o f e t h y l morphine i n m a l e and female animals of f i v e s p e c i e s . T h e i r r e s u l t s sugg e s t t h a t t h e r e w a s a q u a l i t a t i v e (Km) as w e l l as a q u a n t i t a t i v e change (Vmax) i n t h e drug m e t a b o l i z i n g enzymes. A d i s c r e p a n c y between t h e i n v i t r o f i n d i n g s of a d e c r e a s e i n Nd e m e t h y l a t i o n o m o r p h i n r a n n v i v o r e s u l t s has been r e p o r t e d by A d L e r 5 6 . These r e s u m s s u g g e s t t h a t e i t h e r induct i o n o f microsomaL enzymes, o r no change i n t h e i r s y n t h e s i s o c c u r s d u r i n g morphine t o l e r a n c e , r a t h e r than a d e c r e a s e i n microsomal enzyme s y n t h e s i s as i n v i t r o f i n d i n g s have sugmorphine d i d g e s t e d . A s i n g l e i n j e c t i o n of 3h i b i t s y n t h e s i s of microsomal enzymes i n f e m a L e rats 3qotandinv a r i o u s a n t a g o n i s t s w e r e found t o c o m p e t i t i v e l y i n h i b i t d e m e t h y l a t ion of morphine and 0xymorphone3~. The n o n - a d d i c t i n g a n t i t u s s i v e a g e n t dextromethorphan w a s shown t o be principaLLy e x c r e t e d i n b i l e as d-3-hydroxyN-met33L-morphinan and i t s gLucuronide and suLf a t e c o n j u E k c r e t i o n dynamics f o l l o w i n g m u l t i p l e d o s e s w e r e gates n o t s i g n i f i c a n t L y d i f f e r e n t t h a n a f t e r an i n i t i a l i n j e c t i o n ,
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Some m i s c e l l a n e o u s pharmacological s t u d i e s were a l s o of i n t e r e s t , The pharmacology48f N-methylmorphine h a s been comIt w a s concluded t h a t t h e pared w i t h t h a t of morphine pharmacological d i f f e r e n c e s between t h e two compounds can be expLained e s s e n t i a l l y by t h e i n a b i l i t y o f t h e q u a r t e r n a r y s a l t t o e n t e r t h e c e n t r a l nervous system, Morphinone, which i s proposed t o have o n l y d e p r e s s a n t a c t i v i t y , and t h e s t h u L a n t t h e b a i n e , b o t h dect;yased t i d a l volume b u t had no e f f e c t on oxygen consumption , However, t h e compounds a c t e d d i f f e r e n t l y on s e i z u r e t h r e s h o l d , Morphinone raised t h e t h r e s h o l d w h i l e t h e b a i n e Lowered i t . 111. N a r c o t i c A n t a g o n i s t s - Two recent reviews have appeared which d e a l w i t h t h i s area. One is a m a s t e r f u l overview of t h e e n t i r e f i e l d by MartinLC2w h i l e t h e o t h e r c o n c e r n s i t s e l f t o t h e reLeSiveLy L i m i t e d scope of t h e n a r c o t i c - a n t a g o n i s t analgesics This c l a s s of d r u g s c o n t i n u e s t o be t h e f o c u s of a Large r e s e a r c h e f f o r t , A, Pentazocine - T h i s compound w a s released by t h e FDA i n L967. The d r u g i s n o t covered by t h e H a r r i s o n N a r c o t i c A c t and c l i n i c a l a c c e p t a n e , t o d a t e , a p p e a r s t o be good, Laboratory and c l i n i c a l s t u d i e s c o n t i n u e t o appear. Pentazocine h a s been r e p o r t e d t o be e f f e c t i v e i n re1 i e v i n g 4 e x p e r i m e n t a l p a i n i n man and as a p r e o p e r a t i v e medication a l t h o u g h a h i g h dose w a s a s s o c i a t e d w i t h some i n c i dence of psychotomimetic a c t i v i t y i n t h i s group o f p a t i e n t s , The e f f e c t of p e n t a z o c i n e on a s t r o i n t e s t i n a l f u n c t i o n w a s s t u d i e d i n a n e s t h e t i z e d dogs45. G a s t r i c emptying t i m e w a s slowed a l t h o u g h t h e p y l o r i c s p h i n c t e r w a s n o t a f f e c t e d a t t h e doses u s e d . In t h i s r e g a r d p e n t a z o c i n e d i f f e r s from morphine, B. Cyclazocine - T h i s d r u g c o n t i n u e s t o show promise as an a d j u n c t i n t h e treatment of n a r c o t i c a d d i c t i o n 4 6 , W i d e spread c l i n i c a l t r i a l s ?re s t i l l i n p r o ress w i t h continued f a v o r a b l e results. Mule and Gorodetzky$7 s t u d i e d t h e d i s t r i b u t i o n and f a t e of c y c l a z o c i n e i n normal dogs, i n dogs made t o l e r a n t t o t h e d r u g , and i n t o l e r a n t dogs a f t e r a b r u p t withdrawal. Recovery of f r e e and conjugated d r u g i n t h e u r i n e and f e c e s ranged from 40.7% i n t h e a b s t i n e n t animals to 5 8 . 5 % i n t h e t o l e r a n t dogs. The h i g h e r v a l u e i n t o l e r a n t animals w a s due t o an i n c r e a s e d e x c r e t i o n of f r e e d r u g i n t h e f e c e s , There i s some i n d i c a t i o n of s i g n i f i c a n t metabolism. High c o n c e n t r a t i o n s w e r e found i n t h e b r a i n , T h i s i s similar t o t h e f i n d i n g w i t h n a l o r p h i n e and d i f f e r e n t from morphine , The f a i l u r e t o f i n d s i g n i f i c a n t q u a n t i t i e s o f c y c l a z o c i n e i n t h e b r a i n of t h e 24-hour a b s t i n e n t dog s u g g e s t t h a t t h e Long Latency i n t h e o n s e t of a b s t i n e n c e i s n o t due t o r e s i d u a l q u a n t i t i e s of drug. F i n a l l y i t w a s found t h a t c y c l a z o c i n e d i s a p p e a r s more slowly from t h e b r a i n s o f t o l e r a n t animals. T u l l a r and h i s c o l l e a g u e s 4 8 r e p o r t e d t h e p r e p a r a t i o n of a l l
.
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t h e p o s s i b l e s t e r e o i s o m e r s ( o p t i c a l and c i s - , t r a n s - ) of c y c l a z o c i n e and pentazocine. They have been tas n a r cotic-antagonists. In b o t h c a s e s t h e ( - ) - i s o m e r s w e r e cons i d e r a b l y more p o t e n t t h a n t h e ( + > - i s o m e r s . The d i f f e r e n c e s between t h e c i s - and t r a n s - isomers were small. C. Naloxone - T h i s compound a p p e a r s t o be a p u r e a n t a gonist. It has L i t t l e o r no a n a l g e s i c . a c t i v i t y i n animals o r man, does n o t c o n s t r i c t p u p i l s o r produce s u b j e c t i and does n o t produce t o l e r a n c e o r p h y s i c a l dependence Naloxone can r e v e r s e t h e d e p r e s s a n t e f f e c t s o f morphine and c y c l a z o c i n e on t h e f l e x 3 6 r e f l e x a t doses which do n o t d i r e c t l y stcmulate the reflex The compound has a l s o been r e p o r t e d t o a n t a g o n i z e t h e r e s p f f a t o r y d e p r e s s a n t and s u b j e c t i v e e f f e c t s of c y c l a z o c i n e i n man and t h e r e s p i r a t o r y d e p r e s s a n t e f f e c t s of p e n t a z o c i n e i n dogs52. D. Miscellaneous - Wuepper and h i s a s s o c i a t e s 5 3 r e p o r t e d t h a t t h e simuLtaneous a d m i n i s t r a t i o n of n a l o r p h i n e o r l e v a l Lorphan w i t h Levorphanol r e s u l t e d i n a marked r e d u c t i o n i n t h e c o n c e n t r a t i o n o f Levorphanol i n t h e b r a i n as compared t o Levorphanol a l o n e . The a n t a g o n i s t s d i d n o t a f f e c t t h e pLasma Levels o f Levorphanol. The combinat i o n of nalorphine51;Tith morphine d i d n o t g i v e s i m i l a r r e s u l t s . I n L964 Simon reported t h a t LevaLLorphan and o t h e r s y n t h e t i c a n a l o g s of morp h i n e wers5potent i n h i b i t o r s o f b a c t e r i a l growth. Greene and Magasanik i n a b e a u t i f u l l y designed and carried o u t s t u d y , have e l u c i d a t e d t h e mechanism through which LevallorDhan LevaLe x e r t s t h i s a c t i o n on W h e r i c h i a c o f i and HeLa cells: LOrDhan c a u s e s an i m m e d i a t e and m x d d e c r e a s e i n i n t r a c e l LuLar ATP, They p r e s e n t evidence t h a t s u g g e s t s t h a t t h e d e crease i n ATP c o n c e n t r a t i o n r e s u l t s from t h e s t i m u l a t i o n of ATPase , I V . Weak A n a l g e s i c s - Chapter 2L on a n t i i n f l a m m a t o r y drugs should a l s o be consuLted f o r a compl-ete review o f c u r r e n t r e s e a r c h i n t h i s c l a s s of compounds, A. S a l i c y l a t e s - The e f f e c t s o f s a l i c y l a t e s on t h e g a s t r i c mucosa have been reviewed by Davenport56. H e concluded t h a t r e a b s o r p t i o n of g a s t r i c s e c r e t i o n s by t h e more permeable mucosal c e l l s i s more i m p o r t a n t i n s a l i c y l a t e hypoa c i d i t y than an a l t e r a t i o n i n t h e s e c r e t o r y mechanisms, T h i s h y p o t h e s i s o f t h e b a c k - d i f f u s i o n of g a s t r i c a c i d w a s supported by t h e d a t a of Brodie and Chase57 who demonstrated t h a t gast r i c HCL b u t n o t n e c e s s a r i l y d i r e c t c o n t a c t of a s p i r i n w i t h t h e r a t mucosa could cause Lesions and hemorrhage, Schoenh o e f e r and Perry58 have demonstrated an i n h i b i t i o n of t h e s y n t h e s i s of glucosamine-6-phosphate i n g a s t r i c mucosal c e l l s of r a t s b u t n o t i n t h e Liver t i s s u e of t h e s a m e a n i m a l s , f o l l o w i n g a s i n g l e Large o r a l dose o f sodium s a l i c y l a t e o r phenylbutazone, They have suggested t h a t t h i s i n h i b i t i o n may i n t e r f e r e w i t h mucoprotein f o r m a t i o n which i n t u r n may be
.
Chap. 4
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43
r e s p o n s i b l e f o r t h e g a s t r i c i n t o l e r a n c e s e e n w i t h t h e s e comD a t a has been p r e s e n t e d t h a t i n d i c a t e s t h a t s a l i c y pounds. l a t e i s a g e n e r a l i n h i b i t o r of p y r i d i n e n u c l e o t i d e - l i n k e 99d e hydrogenase enzymes i n a number of k v i t r o p r e p a r a t i o n s However, Nakaue a n d co-workers r e p o r t e d no change i n c h i c k s u c c i n i c dehydrogenase g g t i v i t y i n animals f e d v a r i o u s Levels of a c e t y l s a l i c y l i c a c i d ++ b u t n o t Tubular r e a b s o r p t i o n of Na', CL-, C a + + , and Mg K+ w a s augmented by acetyLsaLicyLi a c i d b u t n o t by e t t q x y , a c e t y l or hydroxyorthobenzoic acidg1. Brown and Hardy reported t h a t " a n a l g e s i c n e p h r i t i s " may be due t o amidopyrine which causes p a p i L l a r y n e c r o s i s o r phenazone which c a u s e s Phenacetin w a s p e r s i s t e n t ceLLuria and s l i g h t kidney damage. t h e Least damaging t o t h e kidney o f t h e t h r e e compounds tested. New l i g h t has been shed on t h e c o n f l i c t o v e r t h e m e t a boLic f a t e of s a l i c y l a m i d e i n man. Levy and Matsuzawa63 p r e s e n t e d evidence t h a t t h e m e t a b o l i c e x c r e t i o n of s a l i c y l a m i d e w a s predominantly i n t h e form of a s u l f a t e o r g l u c u r o n i d e c o n j u g a t e depending on t h e dose. Sulfate availability a p p e a r s t o be t h e L i m i t i n g f a c t o r , i.e. a t Low d o s e s s a l i c y l a m i d e w a s e x c r e t e d as t h e s u L f a t e and a t h i g h e r d o s e s t h e f r a c t i o n excreted as t h e g l u c u r o n i d e c o n j u g a t e increased. DipropyLacetylsaLicyLic acid w a s found t o have a more i n t e n s e and Longer l a s t i n g a g c l g e s i c a c t i v i t y t h a n t dose of a c e t y L s a L i c y l i c a c i d Faye and co-workers ported t h a t 2-hydroxy-3,6-dimethylbenzoic a c i d and i t s 6i s o p r o p y l d e r i v a t i v e have more a n a l g e s i c e f f e c t i n t h e r a t than a c e t y l s a l i c y l i c a c i d .
.
.
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B. W r a z o l o n e D e r i v a t i v e s - S i g n i f i c a n t a n a l g e s i c a c t i v i t y w a s observed i n r a t s Lollowing t h e o r a l administ r a t i o n of N - m e t hy l a m i d e -N - ( 4 - a n t i p y r y l ) -oxamic a c i d (XVI) and t o a Legger e x t e n t w i t h o t h e r N - ( 4 - a n t i p y r y l ) -0xamic acid amides H (CH ) I I 3 2
.
H C-
3
3 XVII
XVIII
S u b s t i t u t i o n s Of homologous groups for t h e methylamide d e creased a n a l g e s i c potency U n t i l N -butyLamid e - N - ( 4 - a n t i p y r g l ) oxamic a c i d . The N-hexamide d e r i v a t i v e a g a i n possessed h i g h a n a l g e s i c a c t i v i t y . A series of p y r i d a z i n o n e d e r i v a t i v e s w e r e t e s t e d f o r a n a l g e s i c a c t i v i t y i n mice and 2-methyl-6ethoxy-5-dimethylamino-3 (2H)- p y r i d a z i n o n e ( ~ ~ 1 1and ) t h e 4dimethylami 0 analogue w e r e found t o be t w i c e as a c t i v e as aminoPYrineB7. A number of i s o x a z o l e s and r e l a t e d d e r i v a t i v e s
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w e r e found t o have a n a l g e s i c a c t i v i t y 6 8 . The compounds w i t h a p i p e r i d i n o - o r morphoLinoaLkyL s i d e c h a i n w e r e more p o t e n t . Potency w a s increased and t o x i c i t y decreased by o x i d i z i n g t h e s i d e c h a i n t o an amino-aLcohoL such XVIII. 0 II
Pl -0' -CHCOOH I C2H5
XIX
S02NH2
XXI
C. Miscellaneous Agents - EmeLe and S h a ~ ~ a m ar enp~o~ rted t h a t t h e a n a l g e s i c potency i n Laboratory animals of t h e d i ethylaminoethanol s a l t of 2-(4-biphenylyL)-butyric a c i d (XIX) w a s greater t h a n a c e t y l s a l i c y l i c a c i d i n t h r e e of f o u r p r o cedures used. A series of chromone-2-carboxamides such as XX were Less t o x i c a n d more a c t i v e analgesics t h a n a c e t y l s a l i c y Lic a c i d and amidopy76ne i n a c e t i c acid w r i t h i n g and h e a t A series of p a r a - s u b s t i t u t e d phenylinduced p a i n i n mice a c e t o n i t r i L e s and phenylacetamides w e r e a l s o s y n t h e s i z e d and t e s t e d f o r anaLgesic a c t i v i t y 7 l . The 2-p-cumenyL-4(d i e t h y l amino)-2-isopropyL-butyronitrile (XXI) and t h e 2 - ( p - t e r t b u t y l p h e n y l ) d e r i v a t i v e s of t h e n i t r i l e s w e r e more a c t i v e i n t h e mouse h o t pLate t e s t t h a n phenylbutazone.
.
1. 2. 3.
4. 5.
6. 7.
8.
9.
10. 11. 12. 13a.
b. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25 26 27. 28. 29. 30. 31. 32. 33. 34. 35.
36. 37. 38.
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45 Analgetic s Harris, Dewey References R.O.Martin, M.E.Warren and H.Rapoport, Biochemistry 5, 2355 (1967). 89, 1540 (1967) G.Blashke, H.I.Parker and H.Rapoport, J.Am.Chem.Soc. D.H.R.Barton, G.W.Kirby,W.Steglich, T.G.M.Battersby, A.R.Dobson and H.Ramuz, J.Chem.Soc. 2423 (1965). A.R.Battersby, D.M.Fau1kes and R.Binks, J.Chem.Soc. 3323 (1965). A.R.Battersby, J.A.Martin and E.Brockmann-Hanssen, J.Chem.Soc. 1785 (1967). E.Brochmann-Hanssen, B.Nielsen and G.Aadah1, J.Pharm.Sci. 56, 1207 (1967). K.W.Bentley, D.G.Hardy, B.Meek, J.Am.Chem.Soc. 89, 3267-3321 (1967). W.Fulmor, J.E.Lancaster, G.O.Morton, J.J.Brown, D.F.Hawel1, C.T.Nova 89, 3322 (1967). and R.A.Hardy,Jr., J.Am.Chem.Soc. G.F.Blane, A.L.A.Boura, A.E.Fitzgerald and R.E.Lister, Brit.J. Pharmacol. 30, 11 (1967). G.F.Blane and H.E.Dobbs, Brit.J.Pharmaco1. 30, 166 (1967). G.F.Blane, J.Pharm.Pharmacol.~,781 (1967). E.L.May and N.B.Eddy, J.Med.Chem. 2, 851 (1966). J.E.Villarrea1 and M.H.Seevers, Addendum 1. Minutes Committee on Problems of Drug Dependence (1967). J.E.Villarrea1 and M.H.Seevers, Addendum 1. Minutes Committee on Problems of Drug Dependence (1968). M.A.Davis, F.Herr, R.A.Thomas and M.P.Charest, J.Med.Chem. 10, 627 (1967). K.Orzechowska, Arch.Immunol,Ther.Exp. l5, 290 (1967). J.S.Finch and T.J.DeKornfeld, J.Clin.Pharmaco1. 1, 46 (1967). S.Lecolier and G.Trouiller, Chim.Ther. 2, 16 (1967). M.Mousseron, J.M.Kamenka and A-Stenger, Chim.Ther. 2, 95 (1967). T.Seki, Yakugaku Zasshi 87, 301 (1967). C.G.Bergstrom, J.Med.Chem. 10, 440 (1967). P.R.Carrol1 and G.A.Starmer, Brit.J.Pharmaco1. 30, 173 (1967). G.Kroneberg, A.Oberdorf, F.Hoffmeister and W.Wirth, Arch.Pharmaco1. Exp.Patho1. 256, 257 (1967). R.A.Verri, F.G.Graeff and A.P.Corrado, J.Pharm.Pharmaco1. 2, 264 (1967). M.K.Menon and P.C.Dandiya, Psychopharmacologia 2, 437 (1967). J.A.Ross and A.Ashford, J.Pharm.Pharmaco1. l.9, 709 (1967). E.Contreras, L.Tamayo and L.Quijada, Med.Pharmacol.Exp, l6,371(1967) H.Takagi and M.Nakama, Jap.J.Pharmaco1. l6, 483 (1967). T.F.Burks and J.P.Long, J.Pharmacol.Exp.Therap. 156, 267 (1967). T.F.Burks and J.P.Long, Proc.Soc.Exp.Bio1.Med. 125, 227 (1967). M.T.Spoerlein and J.Scrafani, Life Sciences 5, 1549 (1967). I.Yamamoto, R.Inoki, Y.Tamari and K.Iwatsubo, Jap.J.Pharmaco1. 17, 140 (1967). D.H.Clo5et and M.Ratner, J.Neurochem. 15, 17 (1967). S.J.Mule, J.Pharmacol.Exp.Therap. 156, 92 (1967). C.J.Estler, Int.J.Neuropharmaco1. 5, 241 (1967). 28, 426 J.A.Castro and J.R.Gillette, Biochem.Biophys.Res.Commun. (1967). T.K.Adler, J.Pharmaco1.Exp.Therap. 9,585 (1967). R,Kato and A-Takanaka, Chem.Pharm.Bul1. (Tokyo) l5, 1419 (1967). J.Cochin, C.T.Spivak and S.Lipper, Pharmacologist 2, 218 (1967).
Chap. 4
46 39
40 41 42. 43.
44*
45 46a 47 48. 0
0
49. 50. 51. 52 53. 54. 55. 56 57. 58. 59. 60. 61. 62 63 64 65 66. 67. 68. 69 70. 71
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J.J.Kam, A.B.Taddeo and E.J.VanLoon, J.Pharmacol.Exp.Therap. 158, 437 (1967). R.S.Foster, D.J.Jenden and P.Lomax, J,Pharmacol.Exp.Therap. 157, 185 (1967) R.B.Nelson and H.W.Elliott, J.Pharmacol.Exp.Therap, 155, 516 (1967). W.R.Martin, Pharm.Rev. l9, 463 (1967). H.F.Fraser and L.S.Harris, Ann.Rev.Pharmaco1. 1, 277 (1967), R.C.Hamilton, J.W.Dundee, R.S.J.Clarke, W,B,Loan and J.D.Morrison, Brit.J.Anaesth. 2, 490 and 647 (1967). 1.E.Danhof and W.P.Blackmore, Toxicol.Appl.Pharmaco1. 5, 223 (1967). J-H-JafF,Curr.Psychiat.Ther. 1, 147 (1967). S.J.Mule and C.W.Gorodetzky, J.Pharmacol,Exp.Therap, 154, 632 (1966). B.F.Tullar, L.S.Harris, R.L,Perry, A.K.Pierson, W.F.Wzerau and N.F.Albertson, J.Med.Chem. l.0, 383 (1967). D.R.Jasinski, W.R.Martin and C.A.Haertzen, J,Pharmacol.Exp,Therap. 157, 420 (1967). T.K.McClane and W.R.Martin, 1nt.J.Neuropharmacol. 6, 325 (1967). W.R.Martin, D.R.Jasinski and J.D.Sapira, Pharmacologist 9 , 230 (1967). L.S.Harris, Personal communication. K.D.Wuepper, S.Y.Yeh and L.A.Woods, Proc.Soc.Exp.Bio1.Med. 2,1146 (1967) E.J.Simon, Science 144,543 (1964) R.Greene and B-Magasanik,Mol.Pharmaco1. 3, 453 (1967). H.W,Davenport, New Eng,J.Med. 3,1307 (i967). D.A.Brodie and B.J.Chase, Gastroenterology 53, 604 (1967). P.Schoenhoefer and K.H.Perrey, Med.Pharmaco1. Exp. l.7, 175 (1967). P.D.Dawkins, B.J.Gould, J.A.Sturman and M.J.H.Smith, J.Pharm. Pharmacol. l9, 355 (1967). 125, 663 H.S.Nakaue, C.W.Weber and B.L.Reid, Proc.Soc.Exp.Biol.Med. (1967). A.G.Ramsey and H.C.Elliott, Am.J.Physio1. 213, 323 (1967). D.M.Brown and T.L.Hardy, Brit.J.Pharmaco1. 32, 17 (1967). 285 (1967). G.Levy and T.Matsuzawa, J.Pharmaco1.Exp.Therap. 3, J.L.Benoit-Guyod, A.Boucherle, G,Carraz, P.Eyrnard and H-Meunier, Chim.Ther.2, 49 (1967). W.O.Foye, M.D,Baum and D.A.Williams, J.Pharm.Sci. 56, 332 (1967). T.P.Pastukhova-Petyunina, Farmako1.i Toksikol. 30, 326 (1967). T-Takahashi,Y,Maki, H.Kizu, M.Takaya and T.Miki, Yakugaku Zasshi 86, 1168 (1966). H.Kano, L.Adachi, R.Kido and K,Hirose, J.Med.Chem. 10, 411 (1967). J.F.Eme1e and J.E.Shanaman, Arch.int.Pharmacodyn. 170,99 (1967). P-Bastide,J.Vaudeleau, J.Couquelet and P.Tronchi, Therapie 21, 1361 (1966) G.Pala, E.Crescenzi and E-Marazzi-Uberti, Chim.Ther. 2, 221 (1967).
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The p a s t y e a r h a s been unique i n r e c e n t
t i m e s i n t h a t a s u b s t a n t i a l number of new a n a l g e s i c s have become a v a i l a b l e f o r g e n e r a l m e d i c a l u s e i n t h i s c o u n t r y . These incL ude t h e non -narc0 t i c pheno t h i a z i n e m e t ho t r imepr a z i n e , t h e
n a r c o t i c - a n t a g o n i s t a n a l g e s i c pentazocine, t h e mild a n a l g e s i c mefenamic a c i d , and t h e n e u r o L e p t a n a l g e s i c m i x t u r e of f e n t a n y l and d r o p e r i d o l . Although s y n t h e t i c work i n t h e a n a l g e s i c area h a s n o t been l a r g e , some i n t e r e s t i n g new compound classes have appeared which have b o t h p o t e n t i a l c l i n i c a l u s e f u l n e s s a n d t h e o r e t i c a L importance i n o u r s e a r c h f o r an u n d e r s t a n d i n g o f how a n a l g e s i c s act. 11. S t r o n g AnaLgesics
-
A. Mor h i n e L i t t l e new i n t h e way of s y n t h e t i c work w a s p u b l i s h +--Ti e i n t is area. However, Rapoport and h i s groupLy2 have continued t h e i r e l e g a n t work on t h e b i o s y n t h e s i s o f t h e E a r l i e r B a t o n and h i s c o l l e a g u e s 3 and opium a l k a l o i d s . B a t t e r s b y and h i s a s s o c i a t e s ' had p u t f o r t h e v i d e n c e t h a t This r e t i c u l i n e ( I ) served as a p r e c u r s o r of t h e b a i n e (11). r o l e h a s now been f i r m l y e s t a b l i s h e d i n f r e s h budding p l a n t s
V
IV
I11
and s e e d l i n g s exposed t o 14C02 f o r s h o r t p e r i o d s u t i l i z i n g gas chromatography w i t h s i m u l t a n e o u s mass and a c t i v i t y measurements f o r a n a l y s i s . The r o u t e t o morphine i s t h e s a m e i n s e e d l i n g s as i n mature p l a n t s and f o l l o w s t h e scheme: C02+reticuLine
+thebaine
+ codeine+morphine
The i n t i m a t e d e t a i l s of t h e c o n v e r s i o n of t h e b a i n e t o c o d e i n e h a s a l s o been worked out2y5. Thebaine (11) i s demethylated t o a p o s t u l a t e d t a u t o m e r i c m i x t u r e of neopinone (111) and c o d e i Although t h e none ( I V ) followed by r e d u c t i o n t o c o d e i n e ( V ) . opium poppy i s c a p a b l e o f d e m e t h y l a t i n g c o d e i n e methyl e t h e r , t h e p l a n t a p p a r e n t l y d o e s n o t u s e t h i s r o u t e and t h e r e p o r t e d i s o l a t i o n of t h i s compound i s a t t r i b u t e d t o t h e r e d u t i o n o f t h e b a i n e i n t h e i s o l a t i o n and p u r i f i c a t i o n p r o c e s s e s
8.
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H a r r i s , Dewey
B. O r i p a v i n e Analogs - A c l a s s i c series of p a p e r s by Bentley and h i s c o l l e a g u e s 7 d e s c r i b e t h e s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s of a w i d e v a r i e t y of s t r u c t u r e s d e r i v e d from D i e L s - A l d e r a d d u c t s of t h e b a i n e . Among t h i s group are found some of t h e most p o t e n t a n a l g e s i c s known. Particular attent i o n should be d i r e c t e d toward t h e f i n e a p p l i c a t i o n of n u c l e a r magnetic r e s o n a n c e s p e c t r o s c o p y , by Fulmor and h i s a s s o c i a t e s g t o e l u c i d a t e t h e s t e r e o c h e m i c a l c o n f i g u r a t i o n s of t h e s e i n teres t i n g compound s . The pharmacology of one of t h e more p o t e n t morphine-Like members of t h i s s e r i e s , e t o r p h i n e (M-99, V I ) , h a s r e c e n t l been more e x t e n s i v e l y d e s c r i b e d by BLane and h i s groupg, L8*ll. Depending on t h e t e s t system t h i s compound proved t o be L , O O O -
A: R=R'=C 2H5 B: R=G, R'=CH HO
R
VII
3
R'=CH C: R=C H 3 7' 3
80,000 t i m e s more p o t e n t t h a n morphine. It w a s q u a l i t a t i v e l y s i m i l a r t o morphine w i t h t h e e x c e p t i o n t h a t Low d o s e s o f e t o r p h i n e d i d n o t produce e x c i t e m e n t o r emesis i n dogsg, The d i s t r i b u t i o n of e t o r p h i n e i n t h e p r e g n a n t r a t w a s compared w i t h t h a t of dihydromorphineLO. E t o r p h i n e i s found t o e n t e r and c o n c e n t r a t e more r a p i d l y t h a n dihydromorphine i n t h e b r a i n s of b o t h t h e mothers and t h e f o e t u s e s . Up t o twenty minutes a f t e r i n t r a m u s c u l a r a d m i n i s t r a t i o n t h e c o n c e n t r a t i o n This of e t o r p h i n e w a s h i g h e r i n t h e b r a i n t h a n i n t h e blood. The may e x p l a i n , i n p a r t , t h e h i g h p o t e n c y of t h i s compound. r a p i d p a s s a g e of e t o r p h i n e a c r o s s t h e pLacentaL b a r r i e r and i t s accumulation i n t h e fetaL b r a i n may a l s o e x p l a i n t h e neon a t a l m o r t a l i t y observed a f t e r Large d o s e s of t h i s d r u g , a phenomenon n o t observed w i t h morphine. Evidence has a l s o been p r e s e n t e d t o show t h a t if one a v o i d s t h e s h a r p a b s o r p t i o n peak of e t o r p h i n e , by g i v i n g t h e d r u g s u b l i n g u a l l y , t h e f e t a l r e s p i r a t o r y d e p r e s s i o n and L e t h a l i t y are much LessLL.
C. Benzomorphans - O f i n t e r e s t i s t h e c o n t i n u e d f i n d i n g i n t h e s e compounds of a s t e r e o s p e c i f i c s e p a r a t i o n between a n a l g e s i c a c t i v i t y , as measured by t h e h o t - p l a t e t e c h n i q u e , and ? $ d i c t i o n L i a b i l i t y as assessed i n t h e monkey. May and Eddy had e a r l i e r report'ed t h e r e s o l u t i o n of c i s - 5 , g - d i e t h y l 2 ' -hydroxy-2-methyl-6,7-benzomorphan ( V I I A ) . The ( + ) - i s o m e r had weak a n a l g e s i c a c t i v i t y b u t a h i g h p h y s i c a l dependence c a p a c i t y (PDC). The ( - ) - i s o m e r had h i g h a n a l g e s i c a c t i v i t y y e t proved t o be n a l o r p h i n e - l i k e ( i . e . p r e c i p i t a t e d a b s t i nence) i n a d d i c t e d monkeys. Similar findings w e r e obtained More r e c e n t l y t h e 5w i t h t h e 5-phenyL compound V I I B L 3 a . propyl-9-methyl d e r i v a t i v e V I I C w a s a l s o resoLved and t e s t e d (.
38
I
Sect.
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CNSAgents
Again, t h e (+) -isomer i s a considerabLy Less p o t e n t a n a l g e s i c than t h e (-) -isomer y e t has a h i g h PDC. (-)-isomer beThe (-)-isomer haves Like n a l o r p h i n e i n a d d i c t e d monkeys of V I I A i n t h e t r a n s -conf i g u r a t ion h a s a l s o befgbprepared. It i s a p o t e n t m e s i c w i t h L i t t l e o r no PDC It had no antagonistic activity. Primary a d d i c t i o n s t u d i e s i n monkeys w e r e carried o u t w i t h both (-1 - c i s - and ( - ) - t r a n s - V I I A . The (-)-cis-compound produced few m G h i n e - l i k e a b s t i n e n c e s i g n s on a b r u p t w i t h drawal a f t e r prolonged a d m i n i s t r a t i o n . The ( - ) -trans-compound produced a t y p i c a l morphine-Like a b s t i n e n c e . D. Miscellaneous - Davis and h i s c o l l e a g u e s L 4 r e p o r t e d a series of a m i t r y p t y l i n e analogs c o n t a i n i n g t h e normeperidine group as t h e b a s i c n i t r o g e n . S e v e r a l o f t h e s e had p o t e n t a n a l g e s i c p r o p e r t i e s , The g e n e r a l s t r u c t u r e i s shown as V I I I . Optimum a c t i v i t y w a s achieved when Y= =CHCH2- and Z i s t h e 0 A: R=CH2-@-OC2H5 CH3CH2!6-@ (NOq) m B : R= S-0-OC2H5
.
.
7
9
VIII
-N3pl Z
,
IX
I
X
dCH2 12N (C2H5)
(332CH2Q(
S u b s t i t u t i n g a phenothiazine o r reversed e s t e r -OCOC2H5. benzhydryl f o r t h e d lbenzocycloheptene s y s t e m Lowered a c t i v i t y . A l s o of i n t e r e s t i n t h e meperidine f i e l d i s t h e r e p o r t L5 t h a t meperid he-N-oxide i s e q u i p o t e n t w i t h meperidine w i t h a Longer d u r a t i o n of a c t i o n . Fentanyl (1x1 t h e meperidine anakg i n t h e n e u r o l e p t a n a l g e s i c mixture Innovar, w a s t e s t e d f o r a n a l g e s i a c t i v i t y i n man and found t o be 50x more p o t e n t than morphine f 6
.
A number of r e p o r t s of new s q t h es i n t h e benzimidaz o l e series (XA) have been r e p o r t e d 7-f4. A s would be exp e c t e d , a c t i v e compounds w e r e o b t a i n e d . The nec s ' t y o f t h e 5 - n i t r o group f o r m a x i m a l a c t i v i t y w a s confirmed f.'f,t8. Subs t i t u t i o n of a 2-thiophenyl (XB) a l s o Lowered a c t i v i t y L g .
A series of L6-(3-amino-L7~-20-dih droxypregnanes having a n a l g e s i c a c t i v i t y have been described28. A s i m i l a r compound,
Chap. 4
Analgetic s
Harris, D e w e y
39 -
X I , w a s s t u d i e d f o r addktion L i a b i l i t y i n m 0 n k e y s l 3 ~ . N o Solus u p p r e s s i o n of a b s t i n e n c e w a s noted up t o L 5 mg/kg. b i l i t y prevented h i g h e r doses b u t s i g n s of m i x e d s t i m u l a t i o n and s e d a t i o n w e r e observed, An a l k a l o i d of t h e voacanga
0
XI11
XIV
s e r i e s , spnopharyngine (XII) , w a s a l s o shown t o have a n a l g e s i c activity The a n a l g e s i a observed w a s unaccompanied by motor i n c o o r d i n a t i o n and w a s n o t antagonized by n a l o r p h i n e . The L , 3 - t h i a z i n e X I 1 1 h a s been r e q q r t e d t o have s t r o n g a n a l g e s i c p r o p e r t i e s i n animals and man The compound has a h i g h s e d a t i v e and a n t i h y p e r t e n s i v e component and a c t s Like morphine on t h e e l e c t r i c a l l y s t i m u l a t e d g u t . Also of i n t e r e s t are t h e amphetamine d e r i v a t i v e aletarnine (XIV) and t h e pyrr o l i d i n e d e r i v a t i v e , p r o f a d o l (XV). Both of t h e s e compounds have been r e p o r t e d t o have a n a l g e s i c p r o p e r t i e s i n animals and man a l t h o u g h aletamine w a s q u i t e weak. P r o f a d o l i s c u r r e n t L y b e i n g e v a l u a t e d a t Lexington f o r a d d i c t i o n L i a b i l i t y , A L e t a mine had no PDC i n a d d i c t e d monkeys and i n pr’mary a d d i c t i o n s t u d i e s no morphine-like a b s t i n e n c e w a s seenL3a. E. Biochemical and Pharmacological C o n s i d e r a t i o n s - A number of p a p e r s appeared which i m p l i c a t e d t h e c e n t r a l a d r e n e r g i c system w i t h a n a l g e s i a . V e r r i and co-workers23 reported t h a t premedication w i t h r e s e r p i n e or a - m e t h y l t y r o s i n e antagonized t h e a n a l g e s i c a c t i o n of morphine i n mice. The c e n t r a l s t i m u l a t i n g a c t i o n of m3f;phine w a s r e d u c e d by p r e treatment a-methyltyrosine On t h e o t h e r hand, Ross and Ashford reported t h a t pretreatment with res erp in e in h i b i t e d t h e a n a l g e s i c a c t i o n of morphine i n t h e t a i l cLip t e s t and p o t e n t i a t e d morphine’s a c t i o n i n t h e h o t p l a t e t e s t . a-Methyldopa p r e t r e a t m e n t prevented t h e i n h i b i t o r y e f f e c t o f r e s e r p i n e on t h e taiL c l i p t e s t and showed a n a l g e s i c a c t i o n i t s e l f i n t h e h o t p l a t e t e s t , C o n t r e r a s and h i s co-workers26 demonstrated t h e a n a l g e s i c a c t i v i t y o f methyldopa and ergonov i n e , and t h a t t o l a z o l i n e can a n t a g o n i z e t h e a n a l g e s i a p r o duced by many n a r c o t i c a n a l g e s i c s . T h i s antagonism appeared t o be c o m p e t i t i v e i n t h a t t h e t o l a z o l i n e block c o u l d be o v e r come by h i h e r doses of meperidine and phenazocine. Takagi and NakamaS7 found a r e d u c t i o n i n mouse b r a i n n o r e p i n e p h r i n e and dopamine foLlowing t h e combined i n j e c t i o n of morphine and nalorphine. Nalorphine a l o n e had no e f f e c t on t h e b r a i n cont e n t of t h e s e amines. Morphine and r e l a t e d a g e n t s have been shown t o cause a release of 5-hydroxytryptamine (5-HT) i n t h e s m a l l i n t e s t i n e
.
.
“$5”
.
40 -
Sect.
I
-
CNS Agents
Biel, Ed.
of t h e d ~ tgh a t corresponds t o t h e i n c r e a s e d i n t e s t i n a l t o n e observed , F u r t h e r e v i d e n c e f o r t h e r o l e of 5-HT i n t h e g a s t r o i n t e s t i n a l e f f e c t s of morphine w e r e demonstrated when it w a s observed t h a t methysergide, a p o t e n t i n h i b i t o r of 5-HT, antagonized t h e f f e c t s of morphine on g a s t r o i n t e s t i n a l prop u l s i o n i n m i c e 29
.
In m i c e 8-azaguanine, an i n h i b i t o r f r o t e i n s y n t h e s i s , antagonized t h e development of t 0 l e r a n c e 3 ~Sp. Morphine i n j e c t i o n s i n h i b i t e d t h e i n c o r p o r a t i o n of14C Leucine i n t o b r a i n p r o t e i n s . T h i s e f f e c t of morphine could be blocked by keeping t h e r a t s a t an ambient temperaty5e of 30° and by t h e s i m u l taneous i n j e c t i o n of n a l o r p h i n e The r e l a t i o n s h i p of morphine's action t o protein synthesis o r nucleic acids i s s t i l l not clear. Mul633 r e p o r t e d t h a t P 32 uptake i n t o c o r t i c a l s l i c e s w a s s t i m u l a t e d by t h e subcutaneous a d m i n i s t r a t i o n o f morphine t o n o n - t o l e r a n t guinea p i g s , Chronic morphine t r e a t m e n t i n h i b i t s t h i s i n c r e a s e d phospholid metabolism. The uptake of P 32 i n t o p o l y p h o s p h o i n o s i t i d e s w a s markedly enhanced by c o r t i c a l s l i c e s from a b s t i n e n t g u i n e a p i g s i n t h e p r e s e n c e of morphine, E s t l e r 3 4 c o r r e l a t e d e x c i t e m e n t produced by morphine i n mice w i t h a decrease i n b r a i n glycogen, and an i n c r e a s e i n b r a i n glycogen o f rats s e d a t e d by an i n j e c t i o n of morphine. R a t i o s o f phosphorylase-a t o t o t a l phosphorylase w a s d i r e c t l y reLated t o changes i n glycogen. A s i n o t h e r s t u d i e s of t h i s t y p e i t i s d i f f i c u l t t o a s c e r t a i n whether t h e biochemical changes w e r e t h e c a u s e o r t h e r e s u l t of t h e observed pharmac o l o g i c a l response, A number o f s t u d i e s c o n c e r n i n g t h e m e t a b o l i c f a t e of morphine and t s analogs have been r e p o r t e d . Thus, C a s t r o and G i L L e t t e 3 & s t u d i e d t h e metabolism o f e t h y l morphine i n m a l e and female animals of f i v e s p e c i e s . T h e i r r e s u l t s sugg e s t t h a t t h e r e w a s a q u a l i t a t i v e (Km) as w e l l as a q u a n t i t a t i v e change (Vmax) i n t h e drug m e t a b o l i z i n g enzymes. A d i s c r e p a n c y between t h e i n v i t r o f i n d i n g s of a d e c r e a s e i n Nd e m e t h y l a t i o n o m o r p h i n r a n n v i v o r e s u l t s has been r e p o r t e d by A d L e r 5 6 . These r e s u m s s u g g e s t t h a t e i t h e r induct i o n o f microsomaL enzymes, o r no change i n t h e i r s y n t h e s i s o c c u r s d u r i n g morphine t o l e r a n c e , r a t h e r than a d e c r e a s e i n microsomal enzyme s y n t h e s i s as i n v i t r o f i n d i n g s have sugmorphine d i d g e s t e d . A s i n g l e i n j e c t i o n of 3h i b i t s y n t h e s i s of microsomal enzymes i n f e m a L e rats 3qotandinv a r i o u s a n t a g o n i s t s w e r e found t o c o m p e t i t i v e l y i n h i b i t d e m e t h y l a t ion of morphine and 0xymorphone3~. The n o n - a d d i c t i n g a n t i t u s s i v e a g e n t dextromethorphan w a s shown t o be principaLLy e x c r e t e d i n b i l e as d-3-hydroxyN-met33L-morphinan and i t s gLucuronide and suLf a t e c o n j u E k c r e t i o n dynamics f o l l o w i n g m u l t i p l e d o s e s w e r e gates n o t s i g n i f i c a n t L y d i f f e r e n t t h a n a f t e r an i n i t i a l i n j e c t i o n ,
.
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Chap. 4
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Some m i s c e l l a n e o u s pharmacological s t u d i e s were a l s o of i n t e r e s t , The pharmacology48f N-methylmorphine h a s been comIt w a s concluded t h a t t h e pared w i t h t h a t of morphine pharmacological d i f f e r e n c e s between t h e two compounds can be expLained e s s e n t i a l l y by t h e i n a b i l i t y o f t h e q u a r t e r n a r y s a l t t o e n t e r t h e c e n t r a l nervous system, Morphinone, which i s proposed t o have o n l y d e p r e s s a n t a c t i v i t y , and t h e s t h u L a n t t h e b a i n e , b o t h dect;yased t i d a l volume b u t had no e f f e c t on oxygen consumption , However, t h e compounds a c t e d d i f f e r e n t l y on s e i z u r e t h r e s h o l d , Morphinone raised t h e t h r e s h o l d w h i l e t h e b a i n e Lowered i t . 111. N a r c o t i c A n t a g o n i s t s - Two recent reviews have appeared which d e a l w i t h t h i s area. One is a m a s t e r f u l overview of t h e e n t i r e f i e l d by MartinLC2w h i l e t h e o t h e r c o n c e r n s i t s e l f t o t h e reLeSiveLy L i m i t e d scope of t h e n a r c o t i c - a n t a g o n i s t analgesics This c l a s s of d r u g s c o n t i n u e s t o be t h e f o c u s of a Large r e s e a r c h e f f o r t , A, Pentazocine - T h i s compound w a s released by t h e FDA i n L967. The d r u g i s n o t covered by t h e H a r r i s o n N a r c o t i c A c t and c l i n i c a l a c c e p t a n e , t o d a t e , a p p e a r s t o be good, Laboratory and c l i n i c a l s t u d i e s c o n t i n u e t o appear. Pentazocine h a s been r e p o r t e d t o be e f f e c t i v e i n re1 i e v i n g 4 e x p e r i m e n t a l p a i n i n man and as a p r e o p e r a t i v e medication a l t h o u g h a h i g h dose w a s a s s o c i a t e d w i t h some i n c i dence of psychotomimetic a c t i v i t y i n t h i s group o f p a t i e n t s , The e f f e c t of p e n t a z o c i n e on a s t r o i n t e s t i n a l f u n c t i o n w a s s t u d i e d i n a n e s t h e t i z e d dogs45. G a s t r i c emptying t i m e w a s slowed a l t h o u g h t h e p y l o r i c s p h i n c t e r w a s n o t a f f e c t e d a t t h e doses u s e d . In t h i s r e g a r d p e n t a z o c i n e d i f f e r s from morphine, B. Cyclazocine - T h i s d r u g c o n t i n u e s t o show promise as an a d j u n c t i n t h e treatment of n a r c o t i c a d d i c t i o n 4 6 , W i d e spread c l i n i c a l t r i a l s ?re s t i l l i n p r o ress w i t h continued f a v o r a b l e results. Mule and Gorodetzky$7 s t u d i e d t h e d i s t r i b u t i o n and f a t e of c y c l a z o c i n e i n normal dogs, i n dogs made t o l e r a n t t o t h e d r u g , and i n t o l e r a n t dogs a f t e r a b r u p t withdrawal. Recovery of f r e e and conjugated d r u g i n t h e u r i n e and f e c e s ranged from 40.7% i n t h e a b s t i n e n t animals to 5 8 . 5 % i n t h e t o l e r a n t dogs. The h i g h e r v a l u e i n t o l e r a n t animals w a s due t o an i n c r e a s e d e x c r e t i o n of f r e e d r u g i n t h e f e c e s , There i s some i n d i c a t i o n of s i g n i f i c a n t metabolism. High c o n c e n t r a t i o n s w e r e found i n t h e b r a i n , T h i s i s similar t o t h e f i n d i n g w i t h n a l o r p h i n e and d i f f e r e n t from morphine , The f a i l u r e t o f i n d s i g n i f i c a n t q u a n t i t i e s o f c y c l a z o c i n e i n t h e b r a i n of t h e 24-hour a b s t i n e n t dog s u g g e s t t h a t t h e Long Latency i n t h e o n s e t of a b s t i n e n c e i s n o t due t o r e s i d u a l q u a n t i t i e s of drug. F i n a l l y i t w a s found t h a t c y c l a z o c i n e d i s a p p e a r s more slowly from t h e b r a i n s o f t o l e r a n t animals. T u l l a r and h i s c o l l e a g u e s 4 8 r e p o r t e d t h e p r e p a r a t i o n of a l l
.
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t h e p o s s i b l e s t e r e o i s o m e r s ( o p t i c a l and c i s - , t r a n s - ) of c y c l a z o c i n e and pentazocine. They have been tas n a r cotic-antagonists. In b o t h c a s e s t h e ( - ) - i s o m e r s w e r e cons i d e r a b l y more p o t e n t t h a n t h e ( + > - i s o m e r s . The d i f f e r e n c e s between t h e c i s - and t r a n s - isomers were small. C. Naloxone - T h i s compound a p p e a r s t o be a p u r e a n t a gonist. It has L i t t l e o r no a n a l g e s i c . a c t i v i t y i n animals o r man, does n o t c o n s t r i c t p u p i l s o r produce s u b j e c t i and does n o t produce t o l e r a n c e o r p h y s i c a l dependence Naloxone can r e v e r s e t h e d e p r e s s a n t e f f e c t s o f morphine and c y c l a z o c i n e on t h e f l e x 3 6 r e f l e x a t doses which do n o t d i r e c t l y stcmulate the reflex The compound has a l s o been r e p o r t e d t o a n t a g o n i z e t h e r e s p f f a t o r y d e p r e s s a n t and s u b j e c t i v e e f f e c t s of c y c l a z o c i n e i n man and t h e r e s p i r a t o r y d e p r e s s a n t e f f e c t s of p e n t a z o c i n e i n dogs52. D. Miscellaneous - Wuepper and h i s a s s o c i a t e s 5 3 r e p o r t e d t h a t t h e simuLtaneous a d m i n i s t r a t i o n of n a l o r p h i n e o r l e v a l Lorphan w i t h Levorphanol r e s u l t e d i n a marked r e d u c t i o n i n t h e c o n c e n t r a t i o n o f Levorphanol i n t h e b r a i n as compared t o Levorphanol a l o n e . The a n t a g o n i s t s d i d n o t a f f e c t t h e pLasma Levels o f Levorphanol. The combinat i o n of nalorphine51;Tith morphine d i d n o t g i v e s i m i l a r r e s u l t s . I n L964 Simon reported t h a t LevaLLorphan and o t h e r s y n t h e t i c a n a l o g s of morp h i n e wers5potent i n h i b i t o r s o f b a c t e r i a l growth. Greene and Magasanik i n a b e a u t i f u l l y designed and carried o u t s t u d y , have e l u c i d a t e d t h e mechanism through which LevallorDhan LevaLe x e r t s t h i s a c t i o n on W h e r i c h i a c o f i and HeLa cells: LOrDhan c a u s e s an i m m e d i a t e and m x d d e c r e a s e i n i n t r a c e l LuLar ATP, They p r e s e n t evidence t h a t s u g g e s t s t h a t t h e d e crease i n ATP c o n c e n t r a t i o n r e s u l t s from t h e s t i m u l a t i o n of ATPase , I V . Weak A n a l g e s i c s - Chapter 2L on a n t i i n f l a m m a t o r y drugs should a l s o be consuLted f o r a compl-ete review o f c u r r e n t r e s e a r c h i n t h i s c l a s s of compounds, A. S a l i c y l a t e s - The e f f e c t s o f s a l i c y l a t e s on t h e g a s t r i c mucosa have been reviewed by Davenport56. H e concluded t h a t r e a b s o r p t i o n of g a s t r i c s e c r e t i o n s by t h e more permeable mucosal c e l l s i s more i m p o r t a n t i n s a l i c y l a t e hypoa c i d i t y than an a l t e r a t i o n i n t h e s e c r e t o r y mechanisms, T h i s h y p o t h e s i s o f t h e b a c k - d i f f u s i o n of g a s t r i c a c i d w a s supported by t h e d a t a of Brodie and Chase57 who demonstrated t h a t gast r i c HCL b u t n o t n e c e s s a r i l y d i r e c t c o n t a c t of a s p i r i n w i t h t h e r a t mucosa could cause Lesions and hemorrhage, Schoenh o e f e r and Perry58 have demonstrated an i n h i b i t i o n of t h e s y n t h e s i s of glucosamine-6-phosphate i n g a s t r i c mucosal c e l l s of r a t s b u t n o t i n t h e Liver t i s s u e of t h e s a m e a n i m a l s , f o l l o w i n g a s i n g l e Large o r a l dose o f sodium s a l i c y l a t e o r phenylbutazone, They have suggested t h a t t h i s i n h i b i t i o n may i n t e r f e r e w i t h mucoprotein f o r m a t i o n which i n t u r n may be
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43
r e s p o n s i b l e f o r t h e g a s t r i c i n t o l e r a n c e s e e n w i t h t h e s e comD a t a has been p r e s e n t e d t h a t i n d i c a t e s t h a t s a l i c y pounds. l a t e i s a g e n e r a l i n h i b i t o r of p y r i d i n e n u c l e o t i d e - l i n k e 99d e hydrogenase enzymes i n a number of k v i t r o p r e p a r a t i o n s However, Nakaue a n d co-workers r e p o r t e d no change i n c h i c k s u c c i n i c dehydrogenase g g t i v i t y i n animals f e d v a r i o u s Levels of a c e t y l s a l i c y l i c a c i d ++ b u t n o t Tubular r e a b s o r p t i o n of Na', CL-, C a + + , and Mg K+ w a s augmented by acetyLsaLicyLi a c i d b u t n o t by e t t q x y , a c e t y l or hydroxyorthobenzoic acidg1. Brown and Hardy reported t h a t " a n a l g e s i c n e p h r i t i s " may be due t o amidopyrine which causes p a p i L l a r y n e c r o s i s o r phenazone which c a u s e s Phenacetin w a s p e r s i s t e n t ceLLuria and s l i g h t kidney damage. t h e Least damaging t o t h e kidney o f t h e t h r e e compounds tested. New l i g h t has been shed on t h e c o n f l i c t o v e r t h e m e t a boLic f a t e of s a l i c y l a m i d e i n man. Levy and Matsuzawa63 p r e s e n t e d evidence t h a t t h e m e t a b o l i c e x c r e t i o n of s a l i c y l a m i d e w a s predominantly i n t h e form of a s u l f a t e o r g l u c u r o n i d e c o n j u g a t e depending on t h e dose. Sulfate availability a p p e a r s t o be t h e L i m i t i n g f a c t o r , i.e. a t Low d o s e s s a l i c y l a m i d e w a s e x c r e t e d as t h e s u L f a t e and a t h i g h e r d o s e s t h e f r a c t i o n excreted as t h e g l u c u r o n i d e c o n j u g a t e increased. DipropyLacetylsaLicyLic acid w a s found t o have a more i n t e n s e and Longer l a s t i n g a g c l g e s i c a c t i v i t y t h a n t dose of a c e t y L s a L i c y l i c a c i d Faye and co-workers ported t h a t 2-hydroxy-3,6-dimethylbenzoic a c i d and i t s 6i s o p r o p y l d e r i v a t i v e have more a n a l g e s i c e f f e c t i n t h e r a t than a c e t y l s a l i c y l i c a c i d .
.
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B. W r a z o l o n e D e r i v a t i v e s - S i g n i f i c a n t a n a l g e s i c a c t i v i t y w a s observed i n r a t s Lollowing t h e o r a l administ r a t i o n of N - m e t hy l a m i d e -N - ( 4 - a n t i p y r y l ) -oxamic a c i d (XVI) and t o a Legger e x t e n t w i t h o t h e r N - ( 4 - a n t i p y r y l ) -0xamic acid amides H (CH ) I I 3 2
.
H C-
3
3 XVII
XVIII
S u b s t i t u t i o n s Of homologous groups for t h e methylamide d e creased a n a l g e s i c potency U n t i l N -butyLamid e - N - ( 4 - a n t i p y r g l ) oxamic a c i d . The N-hexamide d e r i v a t i v e a g a i n possessed h i g h a n a l g e s i c a c t i v i t y . A series of p y r i d a z i n o n e d e r i v a t i v e s w e r e t e s t e d f o r a n a l g e s i c a c t i v i t y i n mice and 2-methyl-6ethoxy-5-dimethylamino-3 (2H)- p y r i d a z i n o n e ( ~ ~ 1 1and ) t h e 4dimethylami 0 analogue w e r e found t o be t w i c e as a c t i v e as aminoPYrineB7. A number of i s o x a z o l e s and r e l a t e d d e r i v a t i v e s
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w e r e found t o have a n a l g e s i c a c t i v i t y 6 8 . The compounds w i t h a p i p e r i d i n o - o r morphoLinoaLkyL s i d e c h a i n w e r e more p o t e n t . Potency w a s increased and t o x i c i t y decreased by o x i d i z i n g t h e s i d e c h a i n t o an amino-aLcohoL such XVIII. 0 II
Pl -0' -CHCOOH I C2H5
XIX
S02NH2
XXI
C. Miscellaneous Agents - EmeLe and S h a ~ ~ a m ar enp~o~ rted t h a t t h e a n a l g e s i c potency i n Laboratory animals of t h e d i ethylaminoethanol s a l t of 2-(4-biphenylyL)-butyric a c i d (XIX) w a s greater t h a n a c e t y l s a l i c y l i c a c i d i n t h r e e of f o u r p r o cedures used. A series of chromone-2-carboxamides such as XX were Less t o x i c a n d more a c t i v e analgesics t h a n a c e t y l s a l i c y Lic a c i d and amidopy76ne i n a c e t i c acid w r i t h i n g and h e a t A series of p a r a - s u b s t i t u t e d phenylinduced p a i n i n mice a c e t o n i t r i L e s and phenylacetamides w e r e a l s o s y n t h e s i z e d and t e s t e d f o r anaLgesic a c t i v i t y 7 l . The 2-p-cumenyL-4(d i e t h y l amino)-2-isopropyL-butyronitrile (XXI) and t h e 2 - ( p - t e r t b u t y l p h e n y l ) d e r i v a t i v e s of t h e n i t r i l e s w e r e more a c t i v e i n t h e mouse h o t pLate t e s t t h a n phenylbutazone.
.
1. 2. 3.
4. 5.
6. 7.
8.
9.
10. 11. 12. 13a.
b. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25 26 27. 28. 29. 30. 31. 32. 33. 34. 35.
36. 37. 38.
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45 Analgetic s Harris, Dewey References R.O.Martin, M.E.Warren and H.Rapoport, Biochemistry 5, 2355 (1967). 89, 1540 (1967) G.Blashke, H.I.Parker and H.Rapoport, J.Am.Chem.Soc. D.H.R.Barton, G.W.Kirby,W.Steglich, T.G.M.Battersby, A.R.Dobson and H.Ramuz, J.Chem.Soc. 2423 (1965). A.R.Battersby, D.M.Fau1kes and R.Binks, J.Chem.Soc. 3323 (1965). A.R.Battersby, J.A.Martin and E.Brockmann-Hanssen, J.Chem.Soc. 1785 (1967). E.Brochmann-Hanssen, B.Nielsen and G.Aadah1, J.Pharm.Sci. 56, 1207 (1967). K.W.Bentley, D.G.Hardy, B.Meek, J.Am.Chem.Soc. 89, 3267-3321 (1967). W.Fulmor, J.E.Lancaster, G.O.Morton, J.J.Brown, D.F.Hawel1, C.T.Nova 89, 3322 (1967). and R.A.Hardy,Jr., J.Am.Chem.Soc. G.F.Blane, A.L.A.Boura, A.E.Fitzgerald and R.E.Lister, Brit.J. Pharmacol. 30, 11 (1967). G.F.Blane and H.E.Dobbs, Brit.J.Pharmaco1. 30, 166 (1967). G.F.Blane, J.Pharm.Pharmacol.~,781 (1967). E.L.May and N.B.Eddy, J.Med.Chem. 2, 851 (1966). J.E.Villarrea1 and M.H.Seevers, Addendum 1. Minutes Committee on Problems of Drug Dependence (1967). J.E.Villarrea1 and M.H.Seevers, Addendum 1. Minutes Committee on Problems of Drug Dependence (1968). M.A.Davis, F.Herr, R.A.Thomas and M.P.Charest, J.Med.Chem. 10, 627 (1967). K.Orzechowska, Arch.Immunol,Ther.Exp. l5, 290 (1967). J.S.Finch and T.J.DeKornfeld, J.Clin.Pharmaco1. 1, 46 (1967). S.Lecolier and G.Trouiller, Chim.Ther. 2, 16 (1967). M.Mousseron, J.M.Kamenka and A-Stenger, Chim.Ther. 2, 95 (1967). T.Seki, Yakugaku Zasshi 87, 301 (1967). C.G.Bergstrom, J.Med.Chem. 10, 440 (1967). P.R.Carrol1 and G.A.Starmer, Brit.J.Pharmaco1. 30, 173 (1967). G.Kroneberg, A.Oberdorf, F.Hoffmeister and W.Wirth, Arch.Pharmaco1. Exp.Patho1. 256, 257 (1967). R.A.Verri, F.G.Graeff and A.P.Corrado, J.Pharm.Pharmaco1. 2, 264 (1967). M.K.Menon and P.C.Dandiya, Psychopharmacologia 2, 437 (1967). J.A.Ross and A.Ashford, J.Pharm.Pharmaco1. l.9, 709 (1967). E.Contreras, L.Tamayo and L.Quijada, Med.Pharmacol.Exp, l6,371(1967) H.Takagi and M.Nakama, Jap.J.Pharmaco1. l6, 483 (1967). T.F.Burks and J.P.Long, J.Pharmacol.Exp.Therap. 156, 267 (1967). T.F.Burks and J.P.Long, Proc.Soc.Exp.Bio1.Med. 125, 227 (1967). M.T.Spoerlein and J.Scrafani, Life Sciences 5, 1549 (1967). I.Yamamoto, R.Inoki, Y.Tamari and K.Iwatsubo, Jap.J.Pharmaco1. 17, 140 (1967). D.H.Clo5et and M.Ratner, J.Neurochem. 15, 17 (1967). S.J.Mule, J.Pharmacol.Exp.Therap. 156, 92 (1967). C.J.Estler, Int.J.Neuropharmaco1. 5, 241 (1967). 28, 426 J.A.Castro and J.R.Gillette, Biochem.Biophys.Res.Commun. (1967). T.K.Adler, J.Pharmaco1.Exp.Therap. 9,585 (1967). R,Kato and A-Takanaka, Chem.Pharm.Bul1. (Tokyo) l5, 1419 (1967). J.Cochin, C.T.Spivak and S.Lipper, Pharmacologist 2, 218 (1967).
Chap. 4
46 39
40 41 42. 43.
44*
45 46a 47 48. 0
0
49. 50. 51. 52 53. 54. 55. 56 57. 58. 59. 60. 61. 62 63 64 65 66. 67. 68. 69 70. 71
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