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Chapter 44 Pressor Alkaloids
CHAPTER44 Pressor Alkaloids
I<. I<. CHEN The
illy Research Laboratories, E l i Lilly anc Company, Indianapolis, Indiana
Page I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 11. Aromatic Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 1. Phenalkyl Amines., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 2. Hydroxyphenalkylamine, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 111. Alkyl Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 IV. Indolealkyl Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 1. Indolethyl Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 2. Hydroxyindolethyl Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 V. Synthetic Products of Medicinal Interest.. . . . . . . . . . . . . . . . . . . . . 235 1. Aromatic Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 2. Alkyl Amines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 T’I. Structure-Activity Relationship. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 VII. Optical Isomerism-Activity Relationship . . . . . . . . . . . . . . . . . . . . . . . . 238 VIII. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
I. Introduction Certain alkaloids which occur in plants or animals are capable of raising blood pressure-hence pressor alkaloids. Some of them, particularly the aromatic and aliphatic amines when administered t o the animal body, elicit responses of the visceral organs similar t o those evoked by stimulation of sympathetic nerves. They are, therefore, called sympathomimetic amines. Their general effects are dilatation of the pupil, acceleration of the heart rate, relaxation of the bronchioles, constriction of blood vessels, and inhibition of gastrointestinal peristalsis. The rise of blood pressure may he due to constriction of blood vessels, or stimulation of the heart beat, or 110th. In addition t o the sympathomimetic action, a fern bases have a stimulating action on the central nervous system. Other bases, particularly the indole derivatives, act directly on the smooth muscle organs. They raise the blood pressure, constrict blood vessels, augment cardiac contractions, and excite the movements of intestines and the uterus. Several products play an important role in the physiology of the animal body. A number of the pressor alkaloids and many of their synthetic analogs are widely used in medicine. The literature on the entire group 3f these substances is so extensive that it is impossible t o quote all the im229
230
K. K. CHEN
portant references. Alkaloids which have a more complicated pressor action, such as nicotine, are not included in this discussion.
11. Aromatic Amines 1. PHENALKYL AMINES
p-Phenethylamine (I) is a putrefaction product of ox pancreas and gelatin (l),of egg albumin (2), of mackerel (3), and of edible Boletus (4); it occurs in both European and American mistletoe (5, 6) and in some New Zealand species of Acacia (7); and it is recognizable during ripening of Emmental cheese (8). Biologically it is formed by decarboxylation of phenylalanine as demonstrated in lupine seeds (9), The sympathomimetic action of 0-phenethylamine is not as complete as that of other bases although its pressor activity is relatively high (10). For example, when this amine is applied to the eye of the rabbit and cat, mydriasis does not take place (11). If 0-phenethylamine is given to the rabbit by mouth, a high percentage of phenylacetic acid is recovered in urine (12). This is accomplished by amine oxidase, an enzyme of the body, which oxidizes the base t o the end-product via phenacetaldehyde (13). CH,
I
I1
I11
IV
Ephedrine (11) is an alkaloid of the Chinese medicinal herb Ma Huang which has been identified as Ephedra sinica Stapf (14), and it also occurs in the leaves of the yew, Taxus baccnta L. (15). The natural base is the I-isomer. The Chinese plant contains small amounts of several closely related alkaloids : d-pseudoephedrine, d-norpseudoephedrine (111), l-methylephedrine (IV), and d-methylpseudoephedrine. d-Pseudoephedrine is a diastereoisomer but not an enantiomorph of I-ephedrine. Ephedrine is a sympathomimetic amine since it raises blood pressure, dilates the pupil, stimulates the heart, constricts blood vessels, and relaxes bronchioles and intestines (16). If ephedrine is repeatedly injected by vein into the anesthetized dog or cat, the pressor response diminishes. This is known as tachyphylaxis and is of relatively short duration. Ephed-
PRESSOR ALKALOIDS
231
rine is characterized by its prolonged hypertensive action, as illustrated in Figure 1, and its effectiveness when taken by mouth. The long duration of action may be accounted for by the fact that amine oxidase does not attack ephedrine (17). Preliminary results of a recent investigation indicate that ephedrine is promptly converted to norephedrine in the dog (18). The alkaloid has a stimulating action on the central nervous system when given in excessive amounts (19). Other Ephedra amines-d-pseudoephedrine, 1-methylephedrine, d-norpseudoephedrine, d-methylpseudoephedrine-have a lower pressor action than ephedrine. Ephedrine has many therapeutic uses. It is employed to contract t,he nasal mucous membrane either by local application or per 0s in the treat-
FIG.1. Pressor action of epinephrine and ephedrine in a pithed dog.
ment of common colds, sinusitis, or hay fever (20, 21). It relieves or prevents mild or moderate attacks of bronchial asthma by oral administration (22). Ephedrine is particularly effective in sustaining blood pressure during spinal anesthesia (23). Other ailments which may be ameliorated by ephedrine are narcolepsy, Adams-Stokes syndrome, postural hypotension, and an overdose of depressants such as barbiturates. A suitable solut,ion of ephedrine when instilled into the eye dilates the pupil of a Caucasian whereas in the Negro this reaction is barely perceptible (24). 2. HYDROXYPHENALKYL AMINES
Tyramzne (V) is a common constituent of putrefied organs-human intestines, cod liver, pancreas, egg albumin, and horse meat (25). It is present in Cheddar cheese (as), Emmental cheese (27), and raw-milk cheese (28). The hypertensive action of placental extracts (29) and oi liver extracts (30) is attributed to tyramine. Bacteria such as Escherichia
232
K. K. CHEN
coli, Proteus morganii, and Streptococcusfaecalis are capable of decarboxylating tyrosine to form tyramine (31, 32). That tyramine arises from tyrosine and that N-methyltyramine (VI) and hordenine (VII) are biologically methylated products of tyramine is proven conclusively by feeding radioactive tyrosine to sprouting barley, the tagging being 011 the a-C-atom (33). The active amines can be identified and separated by chromatography (34). Hordenine, the tertiary amine, also occurs in the Mexican cactus Anhalonium (35) and American mistletoe Phoradendron (36).
The peak rise of blood pressure following intravenous injection of tyramine in animals is higher than that of P-phenethylamine (lo), showing the favorable influence of the OH group a t the p-position. The pressor action however, is not sustained (37). Vasoconstriction does not appear t o play an important part in this response (38). The base is characteristically sympathomimetic on other organs. The dog can tolerate almost daily injection of up t o 2 g. for 2!4 years without showing any kidney damage resembling arteriosclerosis and hypertension (39). In the body, tyramine is metabolized to p-hydroxyphenylacetic acid (40) under the influence of amine oxidase. The pressor action of N-methyltyramine and hordenine is lower than that of the primary amine tyramine (10). I n spite of repeated clinical explorations, tyramine has not remained in our armamentarium. Hydroxytyramine (VIII) is a catechol derivative and a product of both animal and plant origin. It can be isolated from the mammalian heart (41) and human urine (42). It occurs as an intermediate of the coloring matter in the broom Cytisus scopariiis Link (43). Conceivably hydroxytyramine is derived from 3,4-dihydroxyphenylalanineby decarboxylation. The specific enzyme, dihydroxyphenylalanine decarboxylase, for catalysis is present in mammalian kidneys (44, 45) and in the rat liver (46). The pressor action of hydroxytyramine is higher than that of tyramine, showing that an additional OH group a t the m-position increases the potency. Its other effects are typically sympathomimetic..
OH
OH VIII
IX
OH
x
PRESSOR ALKALOIDS
233
Epinephrine or adrendine (X) is one of the n-cll-kno\fn drugs in medicine. Oiily recently it was discovered to ( ontaiii 10-18 % norepinephrine or arterenol (IX) n lien prepared from beef adrenal glands (47). Both epinephrine and norepinephrine exist in levorotatory form and are hormones of the body. When sympathetic nerves are clectrically stimulated, epinephrine and norepinephrine are liberated producing the characteristic responees of the visceral organs (48). This accounts for the chemical transmission of nerve impulses, and the two bases xerve as mediators. Both epinephrine and iiorepincphrine are present in the venom of ( ertain toads (49-52). The rise of' blood pressure in thc pithed dog after intravenous injection of epiiiephrine is sharp because its duration is short, as shonn in Figure 1. In an anesthetized dog or cat, the rise is frequently folloned by a fall which is due t o the excitation of vasodilators. The other effects closely torrespond to the stimulation of sympathetic nerves. The term adrenaline (epinephrine) is so widely known that its action has been described as adrenergic-synonymous with sympathomimetic. Epinephrine is not absorbed when given by mouth. The inactivation of the base in vivo by parenteral administration is complicated as revien ed by Bacq (53). The pressor action of epinephrine is potentiated by cocaine (54). On the other hand, insoluble alkaloids of ergot and many synthetic compounds, when administered prior t o epinephrine, induce a fall or reversal of blood pressure -without a primary rise. These antagonists are called adrenergic blocking agents (55). They do not affect the vasodilating action, which accounts for the drop of blood pressure. Therapeutically, epinephrine is a valuable drug for the treatment of allergic diseases including bronchial asthma and hay fever. Because of its vasoconstricting action, it is mixed with local anesthetics in dentistry and surgery t o reduce hemorrhage. Norepinephrine differs pharmacologically from epinephrine in a t least two respects: in ordinary doses it does not produce a secondary fall of blood pressure in anesthetized animals, or reverses it aftcr adrenergic blocking agents; and it slows rather than accelerates the heart rate. Very likely it is metabolized in the body by the same pathway as epinephrine. Clinically it may be useful in the management of hypotension a t shock levels. 111. Alkyl Amines
Isobutylamine (XI) and isoamylamine (XIT) can he obtained by bacterial decarboxylation of valine and of leuciiic, respectively (56). Isoamylamine is thus a constituent of putrid meat (25). It also occurs in kidney extracts (57) and ergot (58). These two bases are the simplest adrenergic sub(CHs)z.CHz.CHz.NH2 XI
(CH3)z*CHz*CHZ*CHZ*hTHz XI1
234
K. K. CHEN
stances, but their activity is low (10). Isoamylamine is definitely more potent than isobutylamine. Both are oxidized by amine oxidase (13).
IV. Indolealkyl Amines 1. INDOLETHYL AMINES
Gramine (XIII) occurs in barley (59) and the leaves of A r u n d o donax L. (60). The alkaloid raises blood pressure but does not dilate the rabbit’s pupil (61). It causes primary stimulation of isolated uterus and intestines. Administration of large doses results in clonic convulsions and excitation of respiratory center (62). Tryptamine (XIV) is found in some species of Acacia (7). It may be formed by putrefaction bacteria from tryptophan-containing media (63). N-Methyltryptamine (XV) is said to be idential with dipterin which occurs in Girgensohnia diptera Bge. and Arthrophytum leptocladum Popov (64). Results of pharmacological studies show that tryptamines are musculotropic and not sympathomimetic (65). They do not dilate the rabbit’s pupil and they contract both the rabbit’s isolated intestine and guinea pig’s uterus. The pressor action of tryptamine is higher than that of N methyltryptamine. The former is metabolized to indoleacetic acid by deamination in the body (13). a C H 2 . N(CIldz H
XI11
a
CH, .CH, .NH
H
~ C I I , ~ C H ~ ~ K H C H ~ H
XIV
XV
CHzOH
I
&j3
CH3.CH.N H * OC
I
1
H
XVI
Ergonovine (ergometrine or ergobasine) (XVI) is a water-soluble alkaloid of ergot (66). The position of t,he double’bond has been revised (67). Ergonovine is one indole derivative that has a sympathomimetic action with a predominantly stimulating action on the uterus (68, 69). It is employed in obstetrics to reduce uterine hemorrhage after childbirth. 2. HYDROXYINDOLETHYL AMINES
Serotonine or enteramine (XVII) is present in the sera of cattle, rabbit, and dog (70), thevenom of B u f o marinus (71), extracts of the posterior sali-
235
PRESSOR ALKALOIDS
vary glands of Octopus vulgaris, and the skin of Discoglossus pictus (72). Bufotenine (XVIII), a tertiary amine, occurs in the venom of the European toad Bufo vulgaris (73), and cinobufotenine or bufotenidine (XIX), in that of the Chinese toad B. gargarizans (74). The latter base is the betaine of bufotenine. All three bases raise blood pressure, cinobufotenine being more active than serotonine or bufotenine (75-77). They cannot be said to have sympathomimetic action because they fail to dilate the pupil and relax intestines. Their effect is directly exerted on the smooth muscle organs. H O ~ C H ~ + C H ~ N H .
H
HO @CH,.CHz*N(CHdz
H XVII
XVIII
-0 @CHz.CH~.6(CHJ~ H
XIX
V. Synthetic Products of Medicinal Interest 1. AROMATIC AMINES Almost all analogs of ephedrine and epinephrine have been synthesized and subjected to pharmacological evaluation. Some of them are used in medicine. The list includes amphetamine or benzedrine (XX), deoxyephedrine (XXI), vonedrine (XXII), propadrine (XXIII), puredrine (XXIV), veritol (XXV), suprifen (XXVI), and neosynephrine (XXVII) . They are advocated as vasoconstrictors in otolaryngology. The marketed form of neosynephrine is the 1-isomer. Amphetamine and deoxyephedrine are now better known for their stimulating action on the central nervous system (78, 79) and are used by persons whose duties call for long periods of alertness. The d-forms of both amines are more effective than the I-forms in this respect. The commercial names of d-deoxyephedrine and d-amphetamine are pervitin and dexedrine, respectively. Two catechol derivatives have been recommended as substitutes for epinephrine. They are epinine (XXVIII) and corbusil (XXIX). 2. ALKYLAMINES Among the synthetic aliphatic amines, tuamine* (XXX), forthane* (XXXI), octin (XXXII), and oenethyl (XXXIII) have a high sympatho-
* ‘Tuamine’ (Tuaminoheptane, Lilly), ‘Forthane’ (Methyl Hexane Amine, Lilly) and ‘Clopane Hydrochloride’ (Cyclopentamine Hydrochloride, Lilly) are trademarks of Eli Lilly and Company.
236
K. K. CHEN
CH3 CH.CHz.NHCH3 I
XXII
XXI
coz
xxv
XXIV
XXIII
CH, CI H .KH CH3
CH3 I
XXVIII
XXVII
XXVI CH, G
I
H * CH .KH 2
CH3 I
CH3 I
CH3
I
CH3.CHz.CHz.CH,.CH,.CH.~H2 CHI.CHz'CH.CHz.CH.IVH2
xxx
XXIX
XXXI CH3
CHa
I I CH,*CH2*CH%*CHz.CHz*CH.NHCH3 (CH3)z.C : CH.CH2.CHz. CH'NHCHa XXXII
XXXIII
CH3
I
8
CH * HCH3 XXXIV
*
mimetic activity. The alicyclic compound clopane" (XXXIV) is more active than ephedrine (80). All these products resemble cphedrine in that they have a methyl group on the carbon atom immediately adjacent t o the basic group. Their pressor action is also prolonged, with development of tachyphylaxis upon repeated intravenous injections. ,ipparently they competitively inhibit the action of amine oxidase (13).
VI. Structure-Activity Relationship The correlation between chemical structure and pharmacological actiyity is more apparent with the pressor alkaloids than n-ith other classes of sub-
PRESSOR ALKALOIDS
237
stances. Reviews on this subject are available (10, 81-84). Pressor action is unique with natural or synthetic alkyl amines, and analogs of phenethylamines and tryptamines. For comparative purposes the pithed cat or dog is the most suitable animal for blood pressure responses. The peak effect and the duration of action following an intrarenous injection are important criteria for classification. Other sympathomimetic or musculotropic effects can be established by other appropriate methods. Of the aliphatic and alicyclic amines, the optimal length of the chain should have seven or eight carbon atoms. Any decrease or increase in the number of carbon atoms results in lowering of the intensity of pressor action. Thus isoamylamine or 4-methyl-2-aminooctane is decidedly less active than forthane or clopane. Prolonged duration of action is acquired by the presence of a methyl group adjacent to the nitrogen atom. Such compounds tend to produce tachyphylaxis and inhibit amine oxidase. Similarly, analogs of p-phenethylamine with a methyl group adjacent to the nitrogen atom have long duration of pressor action and cause tachyphylaxis upon repeated injection. They are not metabolized by amine oxidase. Ephedrine is a typical example. Introduction of a phenolic OH group a t a p - or m-position in the ephedrine or P-phenethylamine molecule results in increase of peak of pressor action, but decrease in duration. The most potent products are those which have an OH group a t both p - and m-positions. They, too, are short acting in spite of a methyl group adjacent to the nitrogen atom. Substitution of an OH group a t the o-position does not have a favorable influence upon the pressor action. Introduction of a secondary OH group on the @-carbonatom of aromatic pressor amines has unpredictable effects. Thus, 6-phenethylamine and tyramine are more active in raising blood pressure than 0-phenethanolamine and p-hydroxyphenethanolamine, respectively. On the other hand, dl-norepinephrine is definitely more active than hydroxytyramine. The presence of the secondary OH group appears to make the compound more firmly sympathomimetic. For example, p-phenethanolamine causes mydriasis while @-phenethylamine does not. The most remarkable feature is the fact that disappearance of this alcoholic group from the molecules of ephedrine and propadrine confers upon these compounds a very high degree of stimulating action on the central nervous system, deoxyephedrine and amphetamine, respectively, being the resulting products. N-Methylation usually weakens the pressor action. Thus N-methylephedrine is less potent than ephedrine. Tyramine is much more active than hordenine. Tryptamine exceeds the activity of its methylated homologs (65). The generalization is, however, not TT ithout exception. Clopane is about one-fourth more active than its primary amine, 2-amino-1cycloFentylpropane (80). If the N-methyl group is replaced by long alkyl chains, the pressor and the sympathomimetic action may be lost (81).
238
K. K. CHEN
Thus, when an isopropyl group is substituted for the methyl group of epinephrine, the resulting compound becomes a depressor drug, causing a fall of blood pressure, although most of its adrenergic properties are retained. A quaternary amine such as cinobufotenine frequently has a high pressor action which, however, is of a mixed nature (ganglionic, etc.). TABLE
1
PRESSOR ACTIVITY O F OPTICAL ISOMERS
Compound
Optical
Animal
Ratio of
Amphetamine sulfate Deoxyephedrine HC1
Dog
Ephedrine HC1
Cat
d-
E-
1.80 1.27
1.4:l
1d-
7.00 2.34
3:l
1d-
0.24
1:6
1000.00 54.18
18:1
1d-
956.00
46:l
1d-
712.20
1d-
2.19 4.21
-
_-
______
-
Pseudoephedrine HC1
Cat
Epinephrine bitartrate
Cat
Norepinephrine bitartrate
Dog
-
Cat _
_
_
Tuamine sulfate a
~
Dog
Ed-
1.34
o
45:1
a
-___
1:2
Direct comparison with the 1-isomer.
VII. Optical Isomerism - Activity Relationship
It has been known for a long time that the Z-isomer of epinephrine is more potent than the d-form. In Table 1, the results of seven pairs of enantiomorphs are presented, which were obtained in the pithed cat or dog (81, 85-87). The l-isomers of amphetamine, deoxyephedrine, and ephedrine all have higher pressor action than their corresponding d-forms, but not t o a great degree. Of the two catechol derivatives, Z-epinephrine and Z-norepinephrine are approximately 18 and 45 times as active as their respect,ive
PRESSOR ALKALOIDS
239
d-isomers. It is especially interesting to observe that d-pseudoephedrine and d-tuamine have six and two times as much pressor action as their Z-forms. d-Tuamine in the form of sulfate is dextrorotatory in aqueous solution due to “acid-effect” (88). As already mentioned above, there is a reversed order of activity of amphetamine and deoxyephedrine upon the central nervous system as contrasted with their sympathomimetic effect. The d-form in each instance is more potent than the Z-isomer t o keep persons awake.
VIII. References 1. M. von Nencki, Pestschr. 40-jiihr. Jubiliibm Prof. V a l e n t i n , B e r n (1876). 2. J. Jeanneret, J . prakt. Chem. 16,353 (1877). 3. A. Gautier and A. Etard, Compt. rend. 94, 1598 (1882); 97, 263 (1883). 4. C. Reuter, Z . physiol. Chem. 78, 167 (1912). 5. M. Leprince, Compt. rend. 146, 940 (1907). 6. A. C. Crawford, J . Am. Med. Assoc. 67, 865 (1911). 7. E. P. White, N e w Zealand J . S c i . Technol. 26B, 137 (1944). 8. E. Winterstein and W. Bissegger, Z . physiol. Chem. 47, 28 (1906). 9. E. Schulze and J. Barbieri, Ber. 12, 1924 (1879). 10. G. Barger and H. H. Dale, J . Physiol. 41, 19 (1910). 11. K. K. Chen, Arch. Internal Med. 39, 404 (1927). 12. M. Guggenheim and H. Loffler, Biochem. 2. 72,325 (1916). 13. H. Blaschko, Pharmacol. Revs. 4,415 (1952). 14. 0. Stapf, K e w B u l l . R o y . Botan. Gardens No. 3, 133 (1927). 15. R . K. Callow, J. M. Gulland, and C. J. Virden, J . Chem. SOC.2138 (1931). 16. K . K. Chen and C. F. Schmidt, J . Pharmacol. E x p t l . Therap. 24, 339 (1924). 17. D. Richter, Biochem. J . 32, 1763 (1938). 18. J. Axelrod and B. B. Brodie, J . Pharmacol. E x p t l . Therap. 106, 372 (1952). 19. S. Morita, Arch. exptl. Pathol. Pharmakol. 78, 218 (1915). 20. G. Fetterolf and M. G. Sponsler, Arch. Otolaryngol. 2, 132 (1925). 21. T. G. Miller, Ann. Clin. M e d . 4, 713 (1926). 22. F. W. Gaarde and C. K . Maytum, Am. J . Med. S c i . 174,635 (1927). 23. R. D. Rudolf and J. D. Graham, Am. J . M e d . S c i . 173, 399 (1927). 24. K. K. Chen and E. J. Poth, Am. J . P h y s . A n t h o p o l . 13, 141 (1929). 25. G. Barger and G. S. Walpole, J. Physiol. 38, 343 (1909). 26. 12. 1,. van Slyke i n d 14;. B. Hart, A m . Chem. J . 30, 1 (1903). 27. E. Winterstein and A. Kung, 2. physiol. Cham. 69, 138 (1909). 28. F. V. Kosikowsky, J . Dairy S c i . 34, 235 (1951). 29. A. E. Dixon and J. Taylor, B r i t . M e d . J . 11, 1156 (1907). 30. F. Grabe, 0. Krayer, and K. Seelkopf, K l i n . Wochschr. 13, 1381 (1934). 31. M. P . Gusakova and S. S. Paikina, 2. Mikrobiol., Epiderniol. Immunitatsforscll. ( U . S . S . R . ) 19, 264 (1937). 32. E. F. Gale, Biochem. J . 34, 846 (1940). 33. E. Leete and L. Marion, Can. J . Chem. 31, 126 (1953). 34. V. Erspamer and G. Falconieri, Naturwissenschaften 39,431 (1952) 35. A. Heffter, Ber. 27, 2975 (1894); 29, 216 (1896); 31, 1193 (1898). 36. A. C. Crawford and W. I<. Watanabc, J . R i d . Chem. 19, 303 (1914). 37. R. K . Chen and W. J . Meek, J . P h n r m x o l . Ezptl. Therap. 28, 59 (1926).
240
K. K. CHEN
38. J. H. Burn, Quart. J . P h a r m . and Pharmacol. 3, 187 (1930); J. Pharmacol. E x p t l . Therap. 46, 75 (1932). 39. R. Enger and H. Lampas, Arch. exptl. Pathol. Pharnzakol. 196, 171 (1940). 40. A. J. Ewins and P. P. Laidlaw, J . Physiol. 41, 78 (1910). 41. M. Goodall, Nature 166, 738 (1950). 42. U. S. von Euler, U. Hamberg, and S. Helliner, Biochem. J . 49, 655 (1951). 43. H. Schmalfuss and A. Heider, Biochem. 2. 236, 226 (1931). 44. H . Blaschko, J. Physiol. 101, 337 (1942). 45. P. Holtz and K . Credner, Arch. exptl. Pathol. Pharmakol. 204, 244 (1947). 46. G. H. Sloane-Stanley, Biochem. J . 45, 556 (1949). 47. M. E . Auerbach and E. Angell, Science 109,537 (1949). 48. U. S. von Euler, Pharmacol. Revs. 3, 247 (1951). 49. J. J. Abel and D . I. Macht, J . Pharmacol. E z p t l . Therap. 3, 319 (1911-12). 50. K . K . Chen and A. L. Chen, Arch. intern. pharnzacodynamie 47, 297 (1934). 51. H. M. Lee and K. K. Chen, J . Pharmacol. E x p t l . Therap. 102, 286 (1951). 52. L. Lasagna, Proc. SOC.E x p t l . Biol. Med. 78, 876 (1951). 53. Z. M. Bacq, Pharmacol. Revs. 1, 1 (1949). 54. A. Frohlich and 0. Loewi, Arch. exptl. Pathol. Pharnzakol. 62, 159 (1910). 55. M. Nickerson, Pharmacol. Revs. 1, 21 (1949). 56. M. Guggenheim, “Die biogenen Amine und ihre Bedeutung fur die Physiologie und Pathologie des pflanzlichen und tierischen Stoffwcchsels,” 4th ed., S. Karger, Basel, 1951, p. 74. 57. V. A. Drill, Proc. SOC.E x p t l . Biol. Med. 49,557 (1942). 58. G. Barger and H . H. Dale, J. Physiol. 38, LXXVII (1909). 59. H. von Euler and H. Hellstrom, 2. physiol. Chcm. 217, 23 (1933). 60. F. P. Massa and G. Stolfi, Arch. sci. biol. ( I t a l y ) 16, 183 (1931). 61. C. E. Powell and K . K . Chen, Proc. SOC. E x p t l . Biol. Med. 58, 1 (1945). 62. J. V. Supniewski and M. Serafinowna, B u l l . intern. m a d . polon. sci. Classe m h d . 479 (1937). 63. A. J. Ewins and P. P. Laidlaw, Proc. Chem. Soc. ( L o n d o n ) 26, 343 (1910). 64. N. K . Yurashevskii, J . Gen. Chem. ( U . S . S . R . ) 9, 595 (1939); 10, 1781 (1940); 11, 157 (1941). 65. K. K . Chen and A. L. Chen, J . Am. P h a r m . Assoc. S c i . E d . 22, 813 (1933). 66. M. S. Kharasch and R . R . Legault, Science 81, 388 (1935); J. Am. Chem. Soc. 57, 1140 (1935). 67. A. Stoll, A. Hofmann, and F. Troxler, Helv. C h i m . A c t a 32, 506 (1949). 68. M. E. Davis, F. I,. Adair, K. K . Chen, and E. E. Swanson, J . Pharntucol. E z p t l . T h e r a p . 54, 398 (1935). 69. G. L. Brown and H. H. Dale, Proc. R o y . SOC.( L o n d o n ) B118, 446 (1935). 70. 31.h1. Rapport, A. A. Green, and I. H. Page, J . Biol.Chem. 176, 1243 (1948). 71. S. Udenfriend, C. T. Clark, and E. Titus, ExpeTientia 8, 379 (1952). 72. V. Erspamer a n d B. Asero, J . Biol. Chem. 200, 311 (1953). 73. H. Wieland, W. Konz, and IT. Mittasch, A,nn. 613, 1 (1931). 74. H. Jensen and I<. K . Chen, J . Biol. Chem. 116,87 (1936). 75. K . K. Chen, H. Jensen, and A . I,. Chen, J . Pharmacol. E x p l l . T h c r u p . 47, 307 (1933). 76. I. H. Page, J . Pharmacol. E z p t l . Therap. 106, 58 (1952). 77. W. A. Freyhurger, B. E. Graham, M. M. Rapport, P. H. Seay, W. M. Govier, 0. F. Swoap, and M. ,J. T‘nnder Brook, J . Pharinacol. E z p f l . T h e r a p . 105, 80 (1-952).
PRESSOR ALKALOIDS
78. 79. 80. 81.
241
A . C. Ivy arid 1,.R . Krasno, War M e d . 1, 15 (1941). A. C. Ivy and F. R. Goetzl, W a r M e d . 3, 60 (1943). E. E. Swanson and K. K. Chen, J . Pharmacol. Exptl. Therap. 93,423 (1948). K. K. Chen, C. K. Wu, and E. Henriksen, J . Pharmacol. Exptl. Therap. 36. 363
(1929). W. H. Hartung, Chem. Revs. 9, 389 (1931). W. H. Hartung, I n d . Eng. Chem. 37, 126 (1945). A. RI. Lands, Pharmacol. Revs . 1, 279 (1949). E. E. Swanson, C. C. Scott, 11. M. Lee, and K. K. Chen, J . Pharmacol. Exptl. Therap. 79, 329 (1943). 86. E. E. Swanson, F. A . Steldt, and K. K. Chen, J . Phurmacol. Exptl. Therap. 8 6 , 70 (1945). 87. E. E. Swanson and K. K. Chen, J . Pliurmaeol. Exptl. Therap. 88, 10 (1946). 88. F. G. Mann and J. W. G. Porter, J . Chem. SOC.456 (1944).
82. 83. 84. 85.
I<. I<. CHEN The
illy Research Laboratories, E l i Lilly anc Company, Indianapolis, Indiana
Page I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 11. Aromatic Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 1. Phenalkyl Amines., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 2. Hydroxyphenalkylamine, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 111. Alkyl Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 IV. Indolealkyl Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 1. Indolethyl Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 2. Hydroxyindolethyl Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 V. Synthetic Products of Medicinal Interest.. . . . . . . . . . . . . . . . . . . . . 235 1. Aromatic Amines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 2. Alkyl Amines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 T’I. Structure-Activity Relationship. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 VII. Optical Isomerism-Activity Relationship . . . . . . . . . . . . . . . . . . . . . . . . 238 VIII. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
I. Introduction Certain alkaloids which occur in plants or animals are capable of raising blood pressure-hence pressor alkaloids. Some of them, particularly the aromatic and aliphatic amines when administered t o the animal body, elicit responses of the visceral organs similar t o those evoked by stimulation of sympathetic nerves. They are, therefore, called sympathomimetic amines. Their general effects are dilatation of the pupil, acceleration of the heart rate, relaxation of the bronchioles, constriction of blood vessels, and inhibition of gastrointestinal peristalsis. The rise of blood pressure may he due to constriction of blood vessels, or stimulation of the heart beat, or 110th. In addition t o the sympathomimetic action, a fern bases have a stimulating action on the central nervous system. Other bases, particularly the indole derivatives, act directly on the smooth muscle organs. They raise the blood pressure, constrict blood vessels, augment cardiac contractions, and excite the movements of intestines and the uterus. Several products play an important role in the physiology of the animal body. A number of the pressor alkaloids and many of their synthetic analogs are widely used in medicine. The literature on the entire group 3f these substances is so extensive that it is impossible t o quote all the im229
230
K. K. CHEN
portant references. Alkaloids which have a more complicated pressor action, such as nicotine, are not included in this discussion.
11. Aromatic Amines 1. PHENALKYL AMINES
p-Phenethylamine (I) is a putrefaction product of ox pancreas and gelatin (l),of egg albumin (2), of mackerel (3), and of edible Boletus (4); it occurs in both European and American mistletoe (5, 6) and in some New Zealand species of Acacia (7); and it is recognizable during ripening of Emmental cheese (8). Biologically it is formed by decarboxylation of phenylalanine as demonstrated in lupine seeds (9), The sympathomimetic action of 0-phenethylamine is not as complete as that of other bases although its pressor activity is relatively high (10). For example, when this amine is applied to the eye of the rabbit and cat, mydriasis does not take place (11). If 0-phenethylamine is given to the rabbit by mouth, a high percentage of phenylacetic acid is recovered in urine (12). This is accomplished by amine oxidase, an enzyme of the body, which oxidizes the base t o the end-product via phenacetaldehyde (13). CH,
I
I1
I11
IV
Ephedrine (11) is an alkaloid of the Chinese medicinal herb Ma Huang which has been identified as Ephedra sinica Stapf (14), and it also occurs in the leaves of the yew, Taxus baccnta L. (15). The natural base is the I-isomer. The Chinese plant contains small amounts of several closely related alkaloids : d-pseudoephedrine, d-norpseudoephedrine (111), l-methylephedrine (IV), and d-methylpseudoephedrine. d-Pseudoephedrine is a diastereoisomer but not an enantiomorph of I-ephedrine. Ephedrine is a sympathomimetic amine since it raises blood pressure, dilates the pupil, stimulates the heart, constricts blood vessels, and relaxes bronchioles and intestines (16). If ephedrine is repeatedly injected by vein into the anesthetized dog or cat, the pressor response diminishes. This is known as tachyphylaxis and is of relatively short duration. Ephed-
PRESSOR ALKALOIDS
231
rine is characterized by its prolonged hypertensive action, as illustrated in Figure 1, and its effectiveness when taken by mouth. The long duration of action may be accounted for by the fact that amine oxidase does not attack ephedrine (17). Preliminary results of a recent investigation indicate that ephedrine is promptly converted to norephedrine in the dog (18). The alkaloid has a stimulating action on the central nervous system when given in excessive amounts (19). Other Ephedra amines-d-pseudoephedrine, 1-methylephedrine, d-norpseudoephedrine, d-methylpseudoephedrine-have a lower pressor action than ephedrine. Ephedrine has many therapeutic uses. It is employed to contract t,he nasal mucous membrane either by local application or per 0s in the treat-
FIG.1. Pressor action of epinephrine and ephedrine in a pithed dog.
ment of common colds, sinusitis, or hay fever (20, 21). It relieves or prevents mild or moderate attacks of bronchial asthma by oral administration (22). Ephedrine is particularly effective in sustaining blood pressure during spinal anesthesia (23). Other ailments which may be ameliorated by ephedrine are narcolepsy, Adams-Stokes syndrome, postural hypotension, and an overdose of depressants such as barbiturates. A suitable solut,ion of ephedrine when instilled into the eye dilates the pupil of a Caucasian whereas in the Negro this reaction is barely perceptible (24). 2. HYDROXYPHENALKYL AMINES
Tyramzne (V) is a common constituent of putrefied organs-human intestines, cod liver, pancreas, egg albumin, and horse meat (25). It is present in Cheddar cheese (as), Emmental cheese (27), and raw-milk cheese (28). The hypertensive action of placental extracts (29) and oi liver extracts (30) is attributed to tyramine. Bacteria such as Escherichia
232
K. K. CHEN
coli, Proteus morganii, and Streptococcusfaecalis are capable of decarboxylating tyrosine to form tyramine (31, 32). That tyramine arises from tyrosine and that N-methyltyramine (VI) and hordenine (VII) are biologically methylated products of tyramine is proven conclusively by feeding radioactive tyrosine to sprouting barley, the tagging being 011 the a-C-atom (33). The active amines can be identified and separated by chromatography (34). Hordenine, the tertiary amine, also occurs in the Mexican cactus Anhalonium (35) and American mistletoe Phoradendron (36).
The peak rise of blood pressure following intravenous injection of tyramine in animals is higher than that of P-phenethylamine (lo), showing the favorable influence of the OH group a t the p-position. The pressor action however, is not sustained (37). Vasoconstriction does not appear t o play an important part in this response (38). The base is characteristically sympathomimetic on other organs. The dog can tolerate almost daily injection of up t o 2 g. for 2!4 years without showing any kidney damage resembling arteriosclerosis and hypertension (39). In the body, tyramine is metabolized to p-hydroxyphenylacetic acid (40) under the influence of amine oxidase. The pressor action of N-methyltyramine and hordenine is lower than that of the primary amine tyramine (10). I n spite of repeated clinical explorations, tyramine has not remained in our armamentarium. Hydroxytyramine (VIII) is a catechol derivative and a product of both animal and plant origin. It can be isolated from the mammalian heart (41) and human urine (42). It occurs as an intermediate of the coloring matter in the broom Cytisus scopariiis Link (43). Conceivably hydroxytyramine is derived from 3,4-dihydroxyphenylalanineby decarboxylation. The specific enzyme, dihydroxyphenylalanine decarboxylase, for catalysis is present in mammalian kidneys (44, 45) and in the rat liver (46). The pressor action of hydroxytyramine is higher than that of tyramine, showing that an additional OH group a t the m-position increases the potency. Its other effects are typically sympathomimetic..
OH
OH VIII
IX
OH
x
PRESSOR ALKALOIDS
233
Epinephrine or adrendine (X) is one of the n-cll-kno\fn drugs in medicine. Oiily recently it was discovered to ( ontaiii 10-18 % norepinephrine or arterenol (IX) n lien prepared from beef adrenal glands (47). Both epinephrine and norepinephrine exist in levorotatory form and are hormones of the body. When sympathetic nerves are clectrically stimulated, epinephrine and norepinephrine are liberated producing the characteristic responees of the visceral organs (48). This accounts for the chemical transmission of nerve impulses, and the two bases xerve as mediators. Both epinephrine and iiorepincphrine are present in the venom of ( ertain toads (49-52). The rise of' blood pressure in thc pithed dog after intravenous injection of epiiiephrine is sharp because its duration is short, as shonn in Figure 1. In an anesthetized dog or cat, the rise is frequently folloned by a fall which is due t o the excitation of vasodilators. The other effects closely torrespond to the stimulation of sympathetic nerves. The term adrenaline (epinephrine) is so widely known that its action has been described as adrenergic-synonymous with sympathomimetic. Epinephrine is not absorbed when given by mouth. The inactivation of the base in vivo by parenteral administration is complicated as revien ed by Bacq (53). The pressor action of epinephrine is potentiated by cocaine (54). On the other hand, insoluble alkaloids of ergot and many synthetic compounds, when administered prior t o epinephrine, induce a fall or reversal of blood pressure -without a primary rise. These antagonists are called adrenergic blocking agents (55). They do not affect the vasodilating action, which accounts for the drop of blood pressure. Therapeutically, epinephrine is a valuable drug for the treatment of allergic diseases including bronchial asthma and hay fever. Because of its vasoconstricting action, it is mixed with local anesthetics in dentistry and surgery t o reduce hemorrhage. Norepinephrine differs pharmacologically from epinephrine in a t least two respects: in ordinary doses it does not produce a secondary fall of blood pressure in anesthetized animals, or reverses it aftcr adrenergic blocking agents; and it slows rather than accelerates the heart rate. Very likely it is metabolized in the body by the same pathway as epinephrine. Clinically it may be useful in the management of hypotension a t shock levels. 111. Alkyl Amines
Isobutylamine (XI) and isoamylamine (XIT) can he obtained by bacterial decarboxylation of valine and of leuciiic, respectively (56). Isoamylamine is thus a constituent of putrid meat (25). It also occurs in kidney extracts (57) and ergot (58). These two bases are the simplest adrenergic sub(CHs)z.CHz.CHz.NH2 XI
(CH3)z*CHz*CHZ*CHZ*hTHz XI1
234
K. K. CHEN
stances, but their activity is low (10). Isoamylamine is definitely more potent than isobutylamine. Both are oxidized by amine oxidase (13).
IV. Indolealkyl Amines 1. INDOLETHYL AMINES
Gramine (XIII) occurs in barley (59) and the leaves of A r u n d o donax L. (60). The alkaloid raises blood pressure but does not dilate the rabbit’s pupil (61). It causes primary stimulation of isolated uterus and intestines. Administration of large doses results in clonic convulsions and excitation of respiratory center (62). Tryptamine (XIV) is found in some species of Acacia (7). It may be formed by putrefaction bacteria from tryptophan-containing media (63). N-Methyltryptamine (XV) is said to be idential with dipterin which occurs in Girgensohnia diptera Bge. and Arthrophytum leptocladum Popov (64). Results of pharmacological studies show that tryptamines are musculotropic and not sympathomimetic (65). They do not dilate the rabbit’s pupil and they contract both the rabbit’s isolated intestine and guinea pig’s uterus. The pressor action of tryptamine is higher than that of N methyltryptamine. The former is metabolized to indoleacetic acid by deamination in the body (13). a C H 2 . N(CIldz H
XI11
a
CH, .CH, .NH
H
~ C I I , ~ C H ~ ~ K H C H ~ H
XIV
XV
CHzOH
I
&j3
CH3.CH.N H * OC
I
1
H
XVI
Ergonovine (ergometrine or ergobasine) (XVI) is a water-soluble alkaloid of ergot (66). The position of t,he double’bond has been revised (67). Ergonovine is one indole derivative that has a sympathomimetic action with a predominantly stimulating action on the uterus (68, 69). It is employed in obstetrics to reduce uterine hemorrhage after childbirth. 2. HYDROXYINDOLETHYL AMINES
Serotonine or enteramine (XVII) is present in the sera of cattle, rabbit, and dog (70), thevenom of B u f o marinus (71), extracts of the posterior sali-
235
PRESSOR ALKALOIDS
vary glands of Octopus vulgaris, and the skin of Discoglossus pictus (72). Bufotenine (XVIII), a tertiary amine, occurs in the venom of the European toad Bufo vulgaris (73), and cinobufotenine or bufotenidine (XIX), in that of the Chinese toad B. gargarizans (74). The latter base is the betaine of bufotenine. All three bases raise blood pressure, cinobufotenine being more active than serotonine or bufotenine (75-77). They cannot be said to have sympathomimetic action because they fail to dilate the pupil and relax intestines. Their effect is directly exerted on the smooth muscle organs. H O ~ C H ~ + C H ~ N H .
H
HO @CH,.CHz*N(CHdz
H XVII
XVIII
-0 @CHz.CH~.6(CHJ~ H
XIX
V. Synthetic Products of Medicinal Interest 1. AROMATIC AMINES Almost all analogs of ephedrine and epinephrine have been synthesized and subjected to pharmacological evaluation. Some of them are used in medicine. The list includes amphetamine or benzedrine (XX), deoxyephedrine (XXI), vonedrine (XXII), propadrine (XXIII), puredrine (XXIV), veritol (XXV), suprifen (XXVI), and neosynephrine (XXVII) . They are advocated as vasoconstrictors in otolaryngology. The marketed form of neosynephrine is the 1-isomer. Amphetamine and deoxyephedrine are now better known for their stimulating action on the central nervous system (78, 79) and are used by persons whose duties call for long periods of alertness. The d-forms of both amines are more effective than the I-forms in this respect. The commercial names of d-deoxyephedrine and d-amphetamine are pervitin and dexedrine, respectively. Two catechol derivatives have been recommended as substitutes for epinephrine. They are epinine (XXVIII) and corbusil (XXIX). 2. ALKYLAMINES Among the synthetic aliphatic amines, tuamine* (XXX), forthane* (XXXI), octin (XXXII), and oenethyl (XXXIII) have a high sympatho-
* ‘Tuamine’ (Tuaminoheptane, Lilly), ‘Forthane’ (Methyl Hexane Amine, Lilly) and ‘Clopane Hydrochloride’ (Cyclopentamine Hydrochloride, Lilly) are trademarks of Eli Lilly and Company.
236
K. K. CHEN
CH3 CH.CHz.NHCH3 I
XXII
XXI
coz
xxv
XXIV
XXIII
CH, CI H .KH CH3
CH3 I
XXVIII
XXVII
XXVI CH, G
I
H * CH .KH 2
CH3 I
CH3 I
CH3
I
CH3.CHz.CHz.CH,.CH,.CH.~H2 CHI.CHz'CH.CHz.CH.IVH2
xxx
XXIX
XXXI CH3
CHa
I I CH,*CH2*CH%*CHz.CHz*CH.NHCH3 (CH3)z.C : CH.CH2.CHz. CH'NHCHa XXXII
XXXIII
CH3
I
8
CH * HCH3 XXXIV
*
mimetic activity. The alicyclic compound clopane" (XXXIV) is more active than ephedrine (80). All these products resemble cphedrine in that they have a methyl group on the carbon atom immediately adjacent t o the basic group. Their pressor action is also prolonged, with development of tachyphylaxis upon repeated intravenous injections. ,ipparently they competitively inhibit the action of amine oxidase (13).
VI. Structure-Activity Relationship The correlation between chemical structure and pharmacological actiyity is more apparent with the pressor alkaloids than n-ith other classes of sub-
PRESSOR ALKALOIDS
237
stances. Reviews on this subject are available (10, 81-84). Pressor action is unique with natural or synthetic alkyl amines, and analogs of phenethylamines and tryptamines. For comparative purposes the pithed cat or dog is the most suitable animal for blood pressure responses. The peak effect and the duration of action following an intrarenous injection are important criteria for classification. Other sympathomimetic or musculotropic effects can be established by other appropriate methods. Of the aliphatic and alicyclic amines, the optimal length of the chain should have seven or eight carbon atoms. Any decrease or increase in the number of carbon atoms results in lowering of the intensity of pressor action. Thus isoamylamine or 4-methyl-2-aminooctane is decidedly less active than forthane or clopane. Prolonged duration of action is acquired by the presence of a methyl group adjacent to the nitrogen atom. Such compounds tend to produce tachyphylaxis and inhibit amine oxidase. Similarly, analogs of p-phenethylamine with a methyl group adjacent to the nitrogen atom have long duration of pressor action and cause tachyphylaxis upon repeated injection. They are not metabolized by amine oxidase. Ephedrine is a typical example. Introduction of a phenolic OH group a t a p - or m-position in the ephedrine or P-phenethylamine molecule results in increase of peak of pressor action, but decrease in duration. The most potent products are those which have an OH group a t both p - and m-positions. They, too, are short acting in spite of a methyl group adjacent to the nitrogen atom. Substitution of an OH group a t the o-position does not have a favorable influence upon the pressor action. Introduction of a secondary OH group on the @-carbonatom of aromatic pressor amines has unpredictable effects. Thus, 6-phenethylamine and tyramine are more active in raising blood pressure than 0-phenethanolamine and p-hydroxyphenethanolamine, respectively. On the other hand, dl-norepinephrine is definitely more active than hydroxytyramine. The presence of the secondary OH group appears to make the compound more firmly sympathomimetic. For example, p-phenethanolamine causes mydriasis while @-phenethylamine does not. The most remarkable feature is the fact that disappearance of this alcoholic group from the molecules of ephedrine and propadrine confers upon these compounds a very high degree of stimulating action on the central nervous system, deoxyephedrine and amphetamine, respectively, being the resulting products. N-Methylation usually weakens the pressor action. Thus N-methylephedrine is less potent than ephedrine. Tyramine is much more active than hordenine. Tryptamine exceeds the activity of its methylated homologs (65). The generalization is, however, not TT ithout exception. Clopane is about one-fourth more active than its primary amine, 2-amino-1cycloFentylpropane (80). If the N-methyl group is replaced by long alkyl chains, the pressor and the sympathomimetic action may be lost (81).
238
K. K. CHEN
Thus, when an isopropyl group is substituted for the methyl group of epinephrine, the resulting compound becomes a depressor drug, causing a fall of blood pressure, although most of its adrenergic properties are retained. A quaternary amine such as cinobufotenine frequently has a high pressor action which, however, is of a mixed nature (ganglionic, etc.). TABLE
1
PRESSOR ACTIVITY O F OPTICAL ISOMERS
Compound
Optical
Animal
Ratio of
Amphetamine sulfate Deoxyephedrine HC1
Dog
Ephedrine HC1
Cat
d-
E-
1.80 1.27
1.4:l
1d-
7.00 2.34
3:l
1d-
0.24
1:6
1000.00 54.18
18:1
1d-
956.00
46:l
1d-
712.20
1d-
2.19 4.21
-
_-
______
-
Pseudoephedrine HC1
Cat
Epinephrine bitartrate
Cat
Norepinephrine bitartrate
Dog
-
Cat _
_
_
Tuamine sulfate a
~
Dog
Ed-
1.34
o
45:1
a
-___
1:2
Direct comparison with the 1-isomer.
VII. Optical Isomerism - Activity Relationship
It has been known for a long time that the Z-isomer of epinephrine is more potent than the d-form. In Table 1, the results of seven pairs of enantiomorphs are presented, which were obtained in the pithed cat or dog (81, 85-87). The l-isomers of amphetamine, deoxyephedrine, and ephedrine all have higher pressor action than their corresponding d-forms, but not t o a great degree. Of the two catechol derivatives, Z-epinephrine and Z-norepinephrine are approximately 18 and 45 times as active as their respect,ive
PRESSOR ALKALOIDS
239
d-isomers. It is especially interesting to observe that d-pseudoephedrine and d-tuamine have six and two times as much pressor action as their Z-forms. d-Tuamine in the form of sulfate is dextrorotatory in aqueous solution due to “acid-effect” (88). As already mentioned above, there is a reversed order of activity of amphetamine and deoxyephedrine upon the central nervous system as contrasted with their sympathomimetic effect. The d-form in each instance is more potent than the Z-isomer t o keep persons awake.
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