Studies of the relationship between molecular structure and hallucinogenic activity

Pharma~oloe) Bu~themt~tr~ & Behavior, Vol 24, pp 335-340 1986 " Ankho International lnc Pnnted m the U S A

0091-~,057/86 $3 00 + 00

Studies of the Relationship Between Molecular Structure and Hallucinogenic Activity DAVID

E

NICHOLS

D e p a r t m e n t o f Medic real C h e m t s t ~ and P h a r m a c o g n o ~y, School o f P h a r m a c y and Pharmac al S( lences Purdue Umver~tty, West L a f a y e t t e , I N 47907

NICHOLS, D E Studies oj the relationship between molecular structure and hallutmogem~ a~tl~tt~ PHARMACOL BIOCHEM BEHAV 24(2) 335-340, 1986 - - T h e nature of the stereochemistry and aromatic ring substltuents and their importance to biological actw~ty for phenethylamme-type hallucinogens is presented The posslbdlty o f a hydrophobic site to bind to the 4-subsutuent and its likely geometry ~s described A brief discussion of the structure-actwity relationships for tryptammes such as psdocln and DMT is also given, with comments about the stereochemlstry of alpha-methyltryptammes Evaluation of a series of N(6)-alkyl-nor-LSD derivatives m&cated that selected members such as N(6)-ethyl, allyl and propyl were as potent as, if not more potent than LSD, both m a two-lever drug discrimination assay in rats, and in man N(6)-alkyl groups longer than n-propyl, such as n-butyl or 2-phenethyl, gave compounds that were greatly reduced in activity Hallucinogen Lysergamides Structure-activity relationships

Nor-LSD derivatives Tryptammes

Phenethylammes

W I T H t h e m a n y r e v i e w s t h a t h a v e a p p e a r e d in r e c e n t y e a r s o n the r e l a t i o n s h i p b e t w e e n s t r u c t u r e a n d a c t l w t y for hall u c i n o g e n i c a g e n t s , a n d with so few i n v e s t i g a t o r s n o w w o r k ing in this area, relatively little n e w i n f o r m a t i o n is a v a i l a b l e H o w e v e r , m o d e s t gains are b e i n g m a d e in o u r u n d e r s t a n d i n g o f this a r e a T h e n e t result is t h a t we h a v e a fairly good k n o w l e d g e o f t h e types o f s t r u c t u r a l c h a n g e s that c a n b e m a d e within all t h e c l a s s e s o f L S D - h k e h a l l u c i n o g e n s O n the o t h e r h a n d , It is not k n o w n w h y activity v a n e s in the w a y it d o e s for t h e s e s t r u c t u r a l m o d i f i c a t i o n s F o r m o s t t h e r e is little u n d e r s t a n d i n g o f w h y a p a r t i c u l a r s t r u c t u r e c h a n g e affects activity As o n e of the first p r e s e n t a t i o n s in this s y m p o s m m , a n a t t e m p t will b e m a d e to b n e f l y s u m m a r i z e w h a t Is k n o w n a b o u t the s t r u c t u r e - a c t w l t y r e l a t i o n s h i p s o f h a l l u c i n o g e n s In a d d i t i o n , s o m e n e w findings will b e n o t e d , especially w i t h regard to r e c e n t w o r k in o u r l a b o r a t o r y with N - s u b s t i t u t e d nor-LSD derivatives It is e a s i e s t to s u m m a r i z 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 b a s e d o n c o m p o u n d type, c o n s i d e r i n g in o r d e r the p h e n e t h y l a m l n e s , t r y p t a m i n e s a n d the e r g o l t n e s T h e r e is n o p a r t i c u l a r r e a s o n for c o v e r a g e in this p a r t i c u l a r o r d e r e x c e p t t h a t the p h e n e t h y l a m t n e s h a v e b e e n the m o s t s y n t h e t i c a l l y a c c e s s i b l e a n d h a v e t h e r e f o r e b e e n s t u d i e d in g r e a t e r detail, at least f r o m t h e m e d i c i n a l c h e m i s t ' s p o i n t of view

Psllocm

early as 1919 [29] T h e e v o l u t i o n of the s u b s t i t u t e d p h e n e t h y l a m l n e s f r o m m e s c a h n e h a s f o c u s e d o n four m a j o r a r e a s t h a t i n c l u d e , (a) o r i e n t a t i o n o f a r o m a t i c ring subs t l t u e n t s , (b) a l k y l a t l o n o f t h e side c h a i n , (c) a l k y l a t l o n of the a m i n o group, a n d (d) c h a r a c t e r o f t h e a r o m a t i c s u b s t l t u e n t s T h e effects o f m e s c a l i n e are v e r y similar to t h o s e o f L S D , b u t it is a c o m p o u n d of v e r y low p o t e n c y , a n d r e q u i r e s a d o s a g e in t h e h u n d r e d s of m l l h g r a m s to p r o d u c e an " e f f e c t i v e " i n t o x i c a t i o n H o w e v e r , within a historical c o n t e x t , m e s c a l i n e m u s t b e v i e w e d as o n e o f the m o r e i m p o r t a n t of the " c l a s s i c a l " h a l l u c i n o g e n s T h e p h e n e t h y l a m l n e s c a n b e c o n s i d e r e d to fall into t w o general c l a s s e s , t h o s e w i t h t h e 3,4,5-trisubstltUtlOn p a t t e r n s e e n in m e s c a l i n e , a n d t h o s e with a 2 , 4 , 5 - t n s u b s t l t U t l o n pattern T h e p o t e n c y of s o m e of t h e c o m p o u n d s m the latter c a t e g o r y has in s o m e c a s e s e x c e e d e d that o f m e s c a l i n e by nearly t h r e e o r d e r s of m a g m t u d e A l t h o u g h t h e s e are t h e t w o m a j o r t y p e s o f biologically i n t e r e s t i n g h a l l u c i n o g e n i c phenethylamlnes, certain mono and dlsubstituted analogues are also a c t i v e W i t h i n b o t h classes, N - a l k y l a t l o n o r N , N - d l a l k y l a t l o n , with only a few e x c e p t i o n s , d r a m a t i c a l l y a t t e n u a t e s activity L i k e w i s e , the side c h a i n is s e n s i t i v e to m o d i f i c a t i o n , alt h o u g h o n e finds t h a t the m o s t p o t e n t c o m p o u n d s all p o s s e s s a m e t h y l a t t a c h e d to the a l p h a side c h a i n c a r b o n T h e side c h a i n c a n also be I n c o r p o r a t e d into a c y c l o p r o p y l ring to give ring-substituted trans-2-phenylcyclopropylamines Stereoselectlvlty for b o t h t y p e s o f t r a n s f o r m a t i o n s is o b s e r v e d T h a t is, for a l p h a m e t h y l g r o u p i n t r o d u c t i o n , the m o r e a c t i v e e n a n t l o m e r p o s s e s s e s t h e R - ( - ) a b s o l u t e c o n f i g u r a t i o n (Fig 2) [26,28] F o r the o n e e x a m p l e w h e r e a trans-2-

PHENETHYLAMINES This large class of h a l l u c i n o g e n i c c o m p o u n d s h a s e v o l v e d out of the p r o t o t y p e s t r u c t u r e o f m e s c a l i n e (Fig 1), a naturally o c c u r r i n g s u b s t a n c e t h a t h a d b e e n s y n t h e s i z e d as

335

336

NICHOLS

H3CO NH2 HaCO"-" OCHa FIG 1 The structure of mescahne

H3CO~NH2 RO""~ OCH3 R=Et R--Pr R=iPr

ESCALINE PROSCALINE ISOPROSCALINE

H~...'NH2 HaCO~ H3C~../~'-OCH3

H~NH2 H3CO,,,~'~ H H3C~f"~-~OCH3

FIG 2 The more active enantlomers of l-(2,5-dlmethoxy-4-methylphenyl)-2-ammopropane (DOM) (left structure) and 2-(2,5-dlmethoxy-4-methylphenyl)cyclopropyl amine (right structure) have the R and IR,2S absolute configurations, respectively, as shown

R

o~

FIG 3 The structures of escallne, proscahne and lsoproscallne, three homologues of mescahne that have been modified at the 4-position to yield compounds that are more potent than mescahne

FIG 4 Based on the out of plane geometry of the 4-methoxy of mescabne, and the increased potency of escahne and proscahne, it ~s suggested that any hydrophoblc site on the receptor at this posztmn may have a geometry which is "normal" to the plane of the aromatic ring binding s~te

p h e n y l c y c l o p r o p y l a m m e was studied as its enanttomers, the IR,2S-(-) c o m p o u n d also p r o v e d to be more active (Fig 2) [18,22] H o w e v e r , the addition of methyl groups to the cyclopropane ring abolished activity in animal models [13], as did e x p a n s i o n o f the ring to a c y c l o b u t a n e [19] A l k y l a t m n of the side chain at the beta position, or alkylation at the alpha posttlon with a group larger than methyl (i e , ethyl, propyl, etc ) also abolished activity [1, 25, 30] F u r t h e r m o r e , a fact noted but not satisfactorily explained, addition of an alpha methyl to 3,4,5-tnsubstltuted c o m p o u n d s increases activity only about two-fold from the parent p h e n e t h y l a m l n e , while a stmllar addition to 2,4,5tnsubstituted c o m p o u n d s can transform an inactive comp o u n d into one with about twenty times the p o t e n c y o f mescahne [27] The alpha methyl clearly has greater importance in the 2,4,5-tnsubstltuted series than in the 3,4,5-series It is n o w also fairly well established that opttmum activity resides in c o m p o u n d s with 2,5- or 3,5-dimethoxy subStltuents R e p l a c e m e n t o f m e t h o x y by e t h o x y at these positions abolishes or dramtically attenuates activity In 2,5dlsubstituted c o m p o u n d s , an e t h o x y or methylthio group ~s better tolerated (1 e , less loss of activity occurs) at the 5-posttion than at the 2-position [15] In 3,4,5-trlsubstltuted c o m p o u n d s an e t h o x y or alkylthlo can be tolerated either at the 3- or the 5-position, but not both, with s o m e retention of activity [14] The unique feature of all the p h e n e t h y l a m l n e s is the dep e n d e n c e of activity on the type of substltuent at the 4-position F o r example, r e p l a c e m e n t of the 4 - m e t h o x y of mescaline with an e t h o x y (Escaline, Fig 3) results in nearly an order o f magnitude increase in oral activtty It seems doubtful that thts is simply due to more favorable blodlstrlbution, since the 4-n-propoxy h o m o l o g u e (Proscahne, Fig 3) is slightly less active than e s c a h n e The 4-isopropoxy derivative has p o t e n c y c o m p a r a b l e to escahne or p r o s c a h n e

All of these, h o w e v e r , have octanol-water partition coefficients l o w e r than the most active c o m p o u n d s m the 2,4,5trlsubstltuted series It has been p r o p o s e d that this enhanced activity may be due to a favorable interaction with a hydrophobic region of the r e c e p t o r [21] Based on the outof-plane g e o m e t r y for the alkoxy substltuent m mescaline [4], this potential hydrophobic site has been illustrated as c o i n o d e n t with a plane normal to the plane of the aromatic ring, as shown below in Fig 4 [18] An interesting variation of this occurs with 2,4,5tnsubstituted c o m p o u n d s Clear increases in activity o c c u r as the 4-substituent is varied from H, to OCH~, to CH~ or longer alkyl groups or to alkylthlo or halogen (Fig 5) H o w ever, one does not see an increase in activity when the 4-substituent is an alkoxy larger than m e t h o x y It has been argued that this may be due to the t e n d e n c y of the oxygen to overlap its n-electrons with the aromatic pl system, which forces the alkoxy group to lie coplanar with the aromatic ring [2] This, in turn, might force the alkyl portion of the alkoxy to protrude into a stencally restricted region of the receptor, whereas ideally it must be twisted out of plane, as noted above The 4-substltuent can probably fill several roles First, it can e n h a n c e general hydrophobiclty and lead to a more favorable penetration of the central nervous system [3] Second, this location is a site for oxidative metabolism such as aromatic hydroxylatlon, O-dealkylation, etc The presence o f a slowly metabolized group, for example ethyl or halogen, will retard clearance of the c o m p o u n d from the body and prolong biological half-life A third role is that of giving the molecule a hydrophobic " a p p e n d a g e " which Is suitably placed for interaction with a postulated hydrophobic region of the r e c e p t o r [21] T h e r e may e v e n be a more critical functional aspect than these, since it appears that the simple p r e s e n c e of a 4-substituent e n h a n c e s activity m a noncon-

STRUCTURE-ACTIVITY RELATIONSHIPS

~

337 !

OCH3

I

NH2

R , ~

CH3

OCH3 H R =H

2,5-DMA

R = OCH3

TMA-2

R = CH 3

DOM

R H

R' H

TRYPTAMINE

R = Br

DOB

5-OH

H

SEROTONIN

R = iBu R =secBu

DOIB DOSB

H

CH 3

DMT

H

CzH5

DET

4 - OH

CH 3

PSILOCIN

CH3

PSILOCYBIN

FIG 5 The structures of a series of 4-substituted 2,5dtmethoxyamphetamme homologues With the exception of the last compound m the series (DOSB) all of these have been found to be active as hallucinogens m man

4-OPO3H

FIG 6 A comparison of the structures of several hallucmogemc tryptamme derivatives w~th tryptamme and serotonm

tmuous way [7] One final point to note is that the 4-substltuent cannot be bulky or b r a n c h e d A m o n g alkyl substltuents, an n-propyl gives o p t i m u m activity, but an lsopropyl is considerably less active, while a tertiary butyl group seems to abolish activity [18] Branching or bulk is most deleterious w h e n it is directly adjacent to the aromatic ring F o r e x a m p l e , w h e n the 4-substituent IS an isobutyl group (Fig 5), activity is largely retained, but with the isomeric sec-butyl, activity is found to drop dramatically [24] Thus, one can see that quite a lot is k n o w n about the structure-activity requirements of p h e n e t h y l a m l n e hallucinogens Why some of these exist is not entirely clear One can imagine an empirically d e v e l o p e d r e c e p t o r model that would be c o m p l e m e n t a r y to these findings, but it is difficult to envision how such a model would apply to a particular r e c e p t o r system Although there is speculation as to how p h e n e t h y l a m l n e s and tryptamines can bind to the same rec e p t o r [18] there is no hard e v i d e n c e to support these ideas A major problem for medicinal chemists studying hallucinogenic p h e n e t h y l a m m e s has been the lack of wellcharacterized m w t r o systems for assay It is difficult, if not impossible, to clearly define molecular requirements for rec e p t o r interactions w h e n the best available models are behavioral paradigms in whole animals One has great difficulty dissecting out the contribution that each molecular modlficauon makes to intrinsic activity, efficacy, pharmacoklnetics, e t c , when the whole animal is used, and used in a way where the response to be m e a s u r e d is ill-defined at best To complicate matters further, it is clear that p h e n e t h y l a m i n e s may interact with a variety of neurotransmltter systems, having effects on transmitter uptake, storage, and release TRYPTAMINES

Hallucinogenic tryptamines are also naturally o c c u m n g

substances that have a long folklonc use by native populations T r y p t a m i n e itself (Fig 6) serves as the basic structural unit for the neurotransmltter serotonln (Fig 6) The hallucinogenic activity of a variety of substituted tryptamines has reinforced the idea that interaction with serotonln receptors is a major and important c o m p o n e n t of the m e c h a n i s m o f action Generally, N,N-dialkyltryptamlnes, such as N , N dlmethyltryptamlne (DMT), N , N - d l e t h y l t r y p t a m m e (DET) or 5 - m e t h o x y - N , N - d t m e t h y l t r y p t a m I n e , lack activity w h e n administered by the oral route, T h e s e materials are more generally smoked or, in native societies, inhaled as snuffs The lack of oral actwlty has been attributed to rapid oxidative metabolism, presumably in the h v e r An Interesting exception, and one of classical importance, is the oral activity of psilocin and psilocybln It is known that the latter compound is hydrolyzed tn v t v o to generate psllocm [11,12], the active species T h e s e c o m p o u n d s o c c u r together as the active c o m p o n e n t s of a n u m b e r of species of p s y c h o a c t i v e m u s h r o o m s T h e y were first isolated by H o f m a n n from P s d o ~ y b e m e x u a n a [10], one of a variety of " s a c r e d mushr o o m s " (Teonanacatl, or flesh of the gods) used by Indians m South A m e r i c a , pnncipally the Aztecs I n v i t r o receptor binding assays have r e v e a l e d that psllocln has lower affinity than certain tryptamlnes that are o x y g e n a t e d at the 5-position [31] H o w e v e r , psllocln has s o m e unique physlco-chemtcal properties which confer it with good potency and activity when administered orally First, for some reason it resists the type of m e t a b o h s m that degrades other N , N - d l a l k y l a t e d tryptamines Second, it seems to have s o m e type of lntramolecular interaction bet w e e n the 4-hydroxy and the side chain amino that lowers its baslcity and increases lipid solubility so that passive entry in the central nervous system is facilitated [17] A r o m a t i c nng substitution in the tryptamlnes has not

338

NICHOLS

0 II

3

(CzHs)zN/C~y- '',, ,..-R H' r~ H

H H

R =H

S - ( + ) - a - ME T H Y L T R Y P T A M I N E

R=OCH 3

(+)-5-OMeAMT

R = Me R =Et R =n-Pr R=Allyl

LSD ETHLAD PROLAD ALLYLAD

FIG 7 The biologically more potent enantlomer of alphamethyltryptamme and 5-methoxy-alpha-methyltryptamlne has the S-(+) absolute configuration

FIG 8 A comparison of the structures of some N(6)-alkyl-nor-LSD derlvatwes The propyl derivative is at least as potent as LSD in a rat assay, with the ethyl and allyl compounds being shghtly more active than LSD

been nearly as rewarding as the work with the phenethylamines With the exception of ring-unsubstltuted compounds, and the 5-methoxy and 4-hydroxy (or phosphoryloxy as m psdocybln) substltuents, no other ringsubstituted compounds have been found active in humans, although only a few have been studied The receptor appears very sensitive to the nature and location of substltuents in the aromatic ring A second structural feature that lends oral activity to tryptamines is the addition of an alpha-methyl Alphamethyltryptamlne (Fig 7) is an inhibitor of monoamine oxidase and is not a substrate for this enzyme [16] Therefore, this ploy effectively prevents the metabolism which is so characteristic of non-alpha-methylated tryptamlnes, and allows distribution to the sites(s) of action Animal studies have shown that it IS the (+) enantlomer of both alphamethyltryptamlne and 5-methoxy-alpha-methyltryptamine that is most active [5,6] In humans, a recent double blind study showed that the (+) isomer of 5methoxy-alpha-methyltryptamlne was about 2-3 times more potent than the ( - ) enantlomer The (+) isomer had about twice the potency of the racemlc material (A T Shulgln, personal communication) Based on work with an asymmetric synthesis of these compounds, both (+) enantlomers possess the S absolute configuration, with stereochemlstry identical to that of S-(+)-amphetamine [20] Not surprisingly, since the alpha-methyltryptamlnes are not readily metabolized, they have a relatively long duration of action The N,N-dlalkyl tryptamlnes, such as DMT or psllocin, have a rapid onset and a relatively brief action, with the effects of the former lasting no more than one hour while the effects of psilocln last 4-6 hours By contrast, the effects of 5-methoxy-alpha-methyltryptamlne can last 18-24 hours, while mescaline and LSD typically have a 10-12 hour duration of action

synthetic d-lyserglc acid dlethylamlde (Fig 8) (d-LSD), the most potent of the hallucinogenic drugs Since the discovery of its biological activity in 1943, thousands of studies have been reported in the literature Of the many structural modiflcatlons which have been made to the LSD structure, none had yielded a compound more potent than LSD itself This report will briefly describe some derivatives of LSD which do appear to have somewhat higher potency than LSD Generally however, one of the unique features of LSD is that its biological activity is so highly dependent on the complete, Intact structure In the prior literature only one compound had been reported to be equlpotent to LSD, the N(l)-acetyl derivative [27], a molecule so labile to hydrolysis that it is cleaved to yield LSD and acetate by treatment with hot water Present evidence indicates that cleavage of the N-acetyl occurs m Vtl,O This compound is probably equlpotent to LSD on a molar basis simply because it serves as a prodrug to LSD Other structural modifications, such as replacement of the diethylamlde function with a variety of N-monoalkyl, N,N-dlalkyl, or N,N-cycloalkylamldes has led only to compounds with reduced activity [27] Parallel interest in our laboratory in the structure-actlvity relationships of dopamlne agonists led us to work on modification of the N(6)-alkyl substltuent in the lysergamldes At about the time we began this work, Nlwaguchl et al [23] published the synthesis of several N(6)-alkyl-nor-LSD derivatives Subsequently, papers appeared which reported studies in the rat uterus and in the rabbit for some of these compounds [8,9] N(6)-n-propyl-nor-LSD appeared particularly interesting in view of the general enhancement of activity that occurs when dopamlne agonlsts possess an n-propyl group attached to the basic mtrogen It was further desired to explore the limits of sterlc tolerance of the receptor(s) for the alkyl substltuent of lysergamldes Using rats trained to dlscNmlnate saline injections from 0 08 mg/kg of LSD tartrate, the two-lever drug discrimination paradigm was used to evaluate the stimulus properties of these drugs and the similarity of their cue to LSD The ED~,, values for LSD, N-ethyl-nor-LSD (ETHLAD), N(6)-n-

ERGOLINES The ergollnes can be viewed as rigid tetracychc tryptamlnes Within this class of compound is found the semi-

STRUCTURE-ACTIVITY

RELATIONSHIPS

p r o p y l - n o r - L S D ( P R O L A D ) , a n d N ( 6 ) - a l l y l - n o r - L S D (ALL Y L A D ) w e r e 30 8, 10 7, 28 4 a n d 9 5 n M / k g , r e s p e c t i v e l y A c t i v i t y d r o p p e d d r a m a t i c a l l y w h e n t h e alkyl was a n isopropyl, n - b u t y l , or 2 - p h e n e t h y l g r o u p F u r t h e r , n o r - L S D was n e a r l y t w o o r d e r s o f m a g n i t u d e less active in this a s s a y t h a n was L S D itself T h e s h a r p d r o p in activity in going f r o m a n n - p r o p y l to a n n - b u t y l suggests t h a t the r e c e p t o r c a n n o t acc o m o d a t e a n alkyl l o n g e r t h a n t h r e e c a r b o n a t o m s T h e m e d i c i n a l c h e m i s t ' s a d a g e " e t h y l , propyl, b u t y l , f u t i l e " s h o u l d p e r h a p s instead be " e t h y l , propyl, b u t y l is futile w" T h e o b s e r v a t i o n of p o t e n c y c o m p a r a b l e to, or g r e a t e r t h a n L S D was o f g r e a t i n t e r e s t It s e e m e d likely, b a s e d on t h e g e n e r a l i z a t i o n in the drug d i s c r i m i n a t i o n a s s a y a n d t h e high p o t e n c i e s o f s e v e r a l o f t h e d e r i v a t i v e s , t h a t t h e s e m i g h t well be m o r e p o t e n t h a l l u c i n o g e n s In m a n t h a n L S D V e r y r e c e n t l y , p r e h m l n a r y studies w e r e carried out (A T Shulgin, p e r s o n a l c o m m u n i c a t i o n ) w h i c h i n d i c a t e d t h a t i n d e e d , the N(6)-ethyl a n d the N ( 6 ) - a l l y l - n o r - L S D d e r i v a t i v e s are s o m e w h a t m o r e p o t e n t t h a n L S D , b y p e r h a p s a f a c t o r o f 2-3 Early results also i n d i c a t e d t h a t N ( 6 ) - p r o p y l - n o r - L S D ret a m s activity c o m p a r a b l e to L S D , but with p e r h a p s less visual d i s t o r t i o n T h e s e p r e l i m i n a r y results w e r e o b t a i n e d a f t e r only a few e x p e r i m e n t s with e a c h c o m p o u n d a n d f u r t h e r e v a l u a t i o n to define the p o t e n c y a n d c h a r a c t e r of t h e s e l y s e r g a m l d e s is u n d e r w a y SUMMARY W e n o w h a v e a g e n e r a l g r a s p of the t y p e s o f s t r u c t u r a l c h a n g e s t h a t c a n be m a d e within the v a r i o u s c l a s s e s of hall u c i n o g e n s In a few c a s e s we b e l i e v e we k n o w w h y t h e s 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 exist, in m o s t we do n o t H o w e v e r , the f o r e g o i n g d i s c u s s i o n has i g n o r e d o n e import a n t q u e s t i o n , t h a t is, in w h a t way do v a r i o u s s t r u c t u r e c h a n g e s modify the q u a h t a t t v e a s p e c t s of the biological ef-

339 fect 9 W h e n d i s c u s s i n g p o t e n c y o f h a l l u c i n o g e n s it h a s b e e n c o m m o n to s p e a k o f " e f f e c t i v e l e v e l s " o r " i n t o x i c a t i o n , " w i t h little r e g a r d as to w h e t h e r this w a s a s e v e r e d i s r u p t i o n o f all s e n s o r y m o d a h t l e s , w a s s e l e c t i v e for o n e or o n l y a few, a n d to w h a t d e g r e e e m o t i o n a n d affect w e r e i n v o l v e d M o r e r e c e n t l y , a t t e n t i o n h a s b e e n paid to t h e n e e d to c h a r a c t e r i z e fully h o w a c h a n g e in c h e m i c a l s t r u c t u r e m a y b r i n g a b o u t a subtle c h a n g e in t h e p s y c h o p h a r m a c o l o g y o f t h e s e s u b s t a n c e s It is c e r t a i n l y clear t h a t if a n y o f t h e s e c o m p o u n d s are e v e n t u a l l y to find t h e i r w a y into m e d i c a l p r a c t i c e , for e x a m p l e as a d j u n c t s to p s y c h o t h e r a p y , t h e y will n e c e s s a r i l y h a v e fairly specific a c t i o n s o n m o o d a n d affect, a n d s h o u l d not d i s r u p t n o r m a l s e n s o r y p r o c e s s i n g As e x e m p l i f i e d b y the N ( 6 ) - a l k y l - n o r - L S D d e r i v a t i v e s rep o r t e d h e r e , it Is possible to find i n t e r e s t i n g biological activity in still u n e x p l o r e d a r e a s of the s t r u c t u r e - a c t i v i t y relationships o f s o m e classes of h a l l u c i n o g e n s H o w e v e r , in spite of this, it s e e m s t h a t m a j o r efforts n e e d to b e d i r e c t e d t o w a r d the p h a r m a c o l o g y , a n d gaining a b e t t e r basic u n d e r s t a n d m g o f the m e c h a n i s m of a c t i o n o f t h e s e s u b s t a n c e s It is to b e h o p e d t h a t the p o t e n t m l i m p o r t a n c e o f t h e s e s u b s t a n c e s as tools to aid in u n d e r s t a n d i n g b r a i n f u n c t i o n will a t t r a c t i n c r e a s i n g r e s e a r c h i n t e r e s t a m o n g n e u r o s c l e n tlsts It is a n a r r o w view i n d e e d to a s s u m e t h a t no c o m p o u n d d e r t v e d f r o m the h a l l u c i n o g e n s will e v e r b e c o m e m e d i c a l l y v a l u a b l e A l t h o u g h this s e e m s to h a v e b e e n the p r e v a i l i n g a t t i t u d e o v e r the past d e c a d e or so, p e r h a p s this will b e g i n to c h a n g e n o w t h a t c o m p o u n d s such as L S D h a v e largely ' f a d e d ' f r o m public view

ACKNOWLEDGEMENT Support for recent work by the National Inshtute on Drug Abuse in the form of grant DA02189 is gratefully acknowledged

REFERENCES 1 Aldous, F A B , B C Barrass, K Brewster, D A Buxton, D 9 Hashlmoto, H , M Hayashl, Y Nakahara, T Nlwaguchl and H Ishn Hyperthermlc effects of d-lysergic acid dlethylamlde M Green, R M Pmder, P Rtch, M Skeels and K J Tutt (LSD) and its derivatives m rabbits and rats Arch Int PharStructure-activity relationships in psychotom~met~c phenylalma~odvn 228: 314-321, 1977 kylammes I M e d ( h e m 17. 1100-1111, 1974 2 Anderson, G M ,III, P A Kollman, L N Domelsmlth and K 10 Hofmann, A , R Hetm, A Brack, H Kobel, A Frey, H Ott, Th Petrzllka and F Troxler Psflocybm und pstlocm, zwel N Houk Methoxy group nonplananty tn o-dtmethoxypsychotrope wtrkstoffe aus mextkamschen rauschpdzen Heir benzenes Simple predltlve models for conformations and rota( h t m A t t a 42: 1557-1572, 1959 ttonal barriers m alkoxyaromatlcs J Am Chem Sot 101" 23442352, 1979 11 Honta, A and L J Weber The enzymatic dephosphorylatlon and oxidation of psdocybm and pstlocm by mammahan tissue 3 Barfknecht, C F , D E Nichols and W J Dunn, III Correlahomogenates Btochem Pharma~ ol 7: 47-54, 1961 tion of psychotom~met~c actlvtty of phenethylammes and amphetamines with 1-octanol/water parhtton coefficients J Med 12 Honta, A and L J Weber Dephosphorylatlon of Pstlocybln in the intact mouse Toxtcol App Pharma< ol 4: 730-737, 1962 ( h e m 18 208-210, 1975 4 Ernst, S R and F W Cagle, Fr Mescahne hydrobromlde 13 Jacob J N and D E Nichols Isomeric cyclopropyl rmgmethylated homologues of trans-2-(2,5-dlmethoxy-4A t t a Crxst B29" 1543-1546, 1973 methylphenyl)cyclopropylamlne, an hallucinogen analogue I 5 Glennon, R A The effect of chtrahty on serotonm receptor Med Chem 25: 526-530, 1982 affimty LlJe ~ t 24. 1487-1492, 1979 6 Glennon, R A , R Young and J M Jacyno Indolealkylamlne 14 Jacob, P , III and A T Shulgm Sulfur analogues of psychotomtmetlc agents Monothlo analogues of mescahne and and phenalkylamlne hallucinogens Effect of a-methyl and isomescahne J Med ( h e m 24 1348-1353, 1981 N-methyl substltuents on behavioral activity Bto~hem Pharm a t o l 32 1267-1273, 1983 15 Jacob, P , III and A T Shulgm Sulfur analogues of psychotomlmet~c agents 2 Analogues of (2,5-dlmethoxy-47 Glennon, R A , R Young, F Benlngton and R D Morln methylphenyl) and (2,5-dtmethoxy-4-ethylphenyl)|soBehavtoral and serotonln receptor properhes of 4-substituted propylamme J Med ( hem 26. 746-752, 1983 denvat|ves o! the hallucinogen l-(2,5-dtmethoxyphenyl)2-ammopropane I Med Chem 25: 1163-1168, 1982 16 Lessm, A W , R F Long and M W Parkes Central sUmulant actions of a-alkyl substituted tryptammes m mtce Br I Phar8 Hashtmoto, H , M Hayashl, Y Nakahara, T Nlwaguchl and ma< ol 24: 4%67, 1965 H Ishu Actions of d-lysergtc a o d dlethylamlde (LSD) and its derivatives on 5-hydroxytryptamme receptors m the isolated utenne smooth muscle of the rat Eur J Pharma~ ol 45 341-348, 1977

340

17 Mtghaccio, G P , T - L N ShIeh, S R Byrn, B A Hathaway and D E Nichols Comparison of solution conformatlonal preferences for the hallucinogens bufotenm and psllocin using 360 MHz proton nmr spectroscopy J Med Chem 24: 206-209, 1981 18 Nichols, D E and R A Glennon Medicinal chemistry and structure-activity relationships of hallucinogens In Hallucinogens Neurochemical, Behavioral and Chnt~al Perspectives, edited by B L Jacobs New York Raven Press, 1984, pp 95-142 19 Nichols, D E , K P Jadhav, R A Oberlender, J E Zabik, J F Bossart, A Hamada and D D Miller Synthesis and evaluation of substituted 2-phenylcyclobutylamlnes as analogues of hallucinogenic phenethylames lack of LSD-hke biological activity J Med Chem 27:1108-111 I, 1984 20 Nichols, D E and D H Lloyd Asymmetnc synthesis of alpha-methyltryptamlne isomers Abstracts of 184th National Meeting of the American Chemical Society, Sept 1982 21 Nichols, D E , A T Shulgln and D C, Dyer Directional hpophlhc character m a series of psychotomlmetlc phenethylamlne derivatives Lift, Set 21: 569-575, 1977 22 Nichols, D E , R Woodard, B Hathaway, M T Lowy and G K W Ylm Resolution and absolute configuatlon of trans-2(2,5-dimethoxy-4-methylphenyl)cyclopropylamIne, an hallucinogen analogue J Med Chem 22" 458-460, 1979 23 Niwaguchl, T , Y Nakahara and H Ishn Studies on lyserglc acid dlethylamide and related compounds IV Syntheses of various amide derivatives of norlyserglc acid and related compounds Yakugaku Za~shi 96: 673-678, 1976

NICHOLS

24 Oberlender, R A , P J Kotharl, D E Nichols and J E Zablk Substltuent branching in phenethylamme-type hallucinogens A comparison of 1-[2,5-dimethoxy-4-(2-butyl) phenyl]-2ammopropane and 1-[2,5-dlmethoxy-4-(2-methylpropyl)phenyl]2-amlnopropane J Med Chem 27: 788--792, 1984 25 Shulgin, A T Psychotomimetlc agents related to mescahne Experlentta 19: 127-128, 1963 26 Shulgm, A T Stereospeofic requirements for halluclnogenesls J Pharm Pharmacol 25" 271-272, 1973 27 ShulgIn, A T Hallucinogens In Burger'~ Medumal (hemtstry, part IlL 4th edition, edited by M E Wolff New York Wiley, 1981, pp 1109-1137 28 Snyder, S H , S Unger, R Blatchley and C F Barfknecht Stereospeofic actions of DOET (2,5-dlmethoxy-4ethylamphetamlne) m man Ar(h Gen P~whlato 31" 103-106, 1974 29 Spath, E Uber die anhalonlum-alkalolde I Anhalon and me~calm Monat~h Chern 40" 129-154, 1919 30 Standndge, R T , H G Howell, J A Gylys, R A Partykaand A T Shulgln Phenylalkylammes with potentml psychotherapeuhc utdlty 1 2-Amino- 1-12,5-dlmethoxy-4methylphenyl)butane J Med Chem 19: 1400--1404, 1976 31 Whltaker, P M and P Seeman HIgh-afflmty ~H-serotomn binding to caudate mhibmon by hallucinogens and serotonlnerglc drugs P~vchophartna~ ologv (Berhn) 59 1-5, 1978