Chiral Genetics of Drugs and Related Compounds

347

Advances in BioChirality G. P/dyi, C. Zucchi and L. Caglioti (Editors) 9 1999 Elsevier Science S.A. All rights reserved.

C H A P T E R 26

Chiral Genetics of Drugs and Related Compounds B61a Noszfil Semmelweis University, Institute of Pharmaceutical Chemistry, H-1092 Budapest, H6gyes E. u. 9., Hungary

Introduction and definitions Receptors of the human body recognise the enantiomeric forms of constitutionally identical compounds as entirely different chemical entities. This fact became strikingly evident by the Contergan (Thalidomide) tragedy [1], when the S-(-) counterpart of R-(+) Thalidomide, a sedative drug has turned out to be embryopathic and teratogenic, after the birth of several thousand malformed babies (Fig. 1). That case has certainly been a major impetus to the evolution of enantiopharmacology, a fledgling science on the interface of stereochemistry and pharmacology [2]. Enantiopharmacology focuses on the biological, pharmacological differences between eutomer and distomer. The former term designates the pharmacologically active, beneficial stereoisomer, whereas the latter one refers to the less active, inactive, or toxic stereoisomer. R-(+)-Thalidomid Contergan| Eutomer Sedative

H

S-(-)-Thalidomid Distomer

Teratogenic Emryopathic

O

0

H

Fig. 1. The eutomeric and distomeric forms of Thalidomide (Contergan|

348 Concerning these terms, two remarks are needed:

.

When a drug molecule has more than one type of biological activity, the same stereoisomer can be eutomer in one of them, and distomer in the other one. Since several drug molecules can have two or more chiral atoms, and concomitantly, not just enantiomers but also, diastereomers with various pharmacological activities, the term, stereopharmacology would be more precise and less restrictive.

The fact that stereoisomers of constitutionally identical compounds can have different biological responses has brought up two related quantitative parameters: the eudismic index (EI) and the eudismic affinity quotient (EAQ) [3]. EI is the activity ratio of the eutomer and distomer in log units. This means that the more stereospecific the drug-receptor interaction, the larger the value of the eudismic index. This has actually been foreseen in Pfeiffer's pioneer work [4], in which he has stated that "the lower the effective dose of a chiral drug, the greater the pharmacological differences of the optical isomers." EAQ provides evidence (or lack) of the active involvement of substituents in homologue series derivatives of the active principle in drug-receptor interactions. If correlation between the EI(log[ICRs0/ICSs0]) values and - l o g ICs0 of the eutomer exists, the involvement of the moiety is proven. Further details of this field can be found in Simonyi's excellent reviews [5-7]. Quantification of enantio-specific pharmacological activity has been done for several compounds. Only a few examples can be cited here. The bioavailability of S-Verapamil is 2-3 times higher than that of R-verapamil [8]. S-amphetamine is 10 times more potent than R-amphetamine in alerting action, but only 2 times more potent than R-amphetamine as a psychotomimetic drug [9]. Not only binding and the related activity, but also the metabolism and elimination can be stereospecific. For example, warfarine, an anticoagulant drug has a 2.5 times longer half-life in its R-form than in its S-form, which is assumed to be due to enantio-discriminative enzyme-binding [5]. The complexity of this issue is nicely exemplified by the ephedrines [10], Table 1. Of the four stereoisomers of the ephedrine family, the second most potent is the

Table 1 Relative pressor activity of diastereomeric ephedrine forms Name

Configuration of the chiral atoms

Relative pressor activity

D(-)Ephedrine L(+)Ephedrine L(+)-Ephedrine D(-) -Ephedrine

1R 2S 1S 2R 1S 2S 1R 2R

36 11 7 1

349

enantiomeric counterpart indeed, instead of one of the diastereomers, as could be expected. Data of this kind certainly raise an experimental remark: when both of the enantiomers (or all of the stereoisomers) appear to have more or less biological activity, (at least at the level of macroscopic observation), the possibility of in vivo racemization (stereo-transformation) must be carefully checked by quantitative, stereo-specific analysis of the administered and excreted compound(s). Enantio-selective binding gains even higher emphasis when activity of the enantiomers is different not only quantitatively, but also, qualitatively [11]. Such observations have been reported for estrone, thyroxine, penicillamine, ketamine, bupivacaine, timolol, indacrinone, picenadol, prilocaine, ibuprofene, etc. Perhaps, the most puzzling observation on ligand-receptor-interactions, and related biological actions is described for odorant molecules. In some cases of these molecules none of the enantiomers can activate the olfactory system, but a certain composition of the volatile(!) odorant stereoisomer molecules can [12]. A practical consequence of the above phenomena can be observed in the pharmaceutical industry. Companies tend to carry out the so called racemic switch, in which drugs that have been approved as racemates, are redeveloped in single-enantiomeric form [13]. The biological aspects of the chiral ligand-receptor interactions have been enriched and modified by the discovery of some endogenous ligands. Drugs, narcotic and psychotropic agents are typically exogenous compounds, produced by plants, or by synthetic and semisynthetic methods. Compounds, exerting the same or similar biological actions, but produced by the human body are their endogenous counterparts. Curiously enough, the endogenous ligands have only been discovered in the past 25 years, decades, if not centuries later than the corresponding exogenous compound. In view of chiral-specific, molecular characterization of drug-receptor interactions, the recent developments of stereo-pharmacological studies seek answer to several questions: 1.

2. 3.

4.

5.

Of all the drug molecules in the various pharmacological classes, what is the percentage of the chiral ones? And what is the analogous figure among narcotic and psychotropic compounds? Among all the drug molecules, which one is the "most chiral"? Which molecule contains the largest percent of chiral centres? It seems reasonable that the more subtle the biological effect, the more likely the specific binding, especially in the central nervous system (CNS). Is this assumption substantiated? Since the narcotic and psychotropic compounds influence neurotransmission in the CNS, they might have structural similarities with endogenous neurotransmitters. What is the extent of these similarities? Are there superimposable moieties of the exogenous and endogenous compounds? Is there chiral-genetic relationship between the exogenous narcotic and psychotropic compounds and their endogenous counterparts?

350

Here we report our attempts to answer these questions. It must be made unmistakably clear that not all of these questions can be satisfactorily replied today.

Results and discussion

Chiral statistics of drugs and related molecules Drug Compendium (Volume 6) of Comprehensive Medicinal Chemistry [14], is a large database of medicinal compounds, with nearly 6000 constitutionally definite chemical entities. The compounds are sorted into 13 major pharmacological classes, and a total of 131 subclasses. The same chemical entity, of course, may appear in more than one class (or subclass). Narcotic and psychotropic drugs as such, however, are not considered in this volume. They were therefore collected from the International Narcotics Control Board's list (Vienna, 1997) [15]. Table 2 enlists the major pharmacological, narcotic and psychotropic classes and six characteristics within each class: the number of subclasses, the total number of compounds, the number of chiral compounds, the percentage of chiral compounds, the name of the "most chiral" compound, and the percentage of chiral carbon atoms in the "most chiral" compound. The term "most chiral" was assigned to those molecules where the percentage of chiral carbon atoms is highest. Phenomena of non-carbon chirality and molecular chirality are sporadic among the drug and related molecules. These categories were therefore neglected here. Evaluation of the data show that 13 of the 131 subclasses contain no chiral compounds at all. Antacids, antiperistaltic, dental caries-prophylactic, pediculicide, repellent, scabicide, carbonic anhydrase inhibitor, depigmentor, vulnerary, spermaticide, thyroid inhibitor, xanthine oxydase inhibitor, cholinesterase inhibitor and radioprotective compounds are all achiral. These subclasses are typically small groups, with an average of 4.6 molecules in a subclass. Many of the compounds are inorganic. Contrary to that, there are 9 subclasses where all the compounds are chiral. (Table 3) The "highly chiral" subclasses are usually populous. On average, 28 compounds belong to the 9 subclasses where all the compounds are chiral. Drug molecules of the hormonal system are characteristically of natural origin, (steroids, peptides and their derivatives, etc.), being therefore understandably chiral. The class, containing the largest number (23) of subclasses, and the largest number of compounds (1211) as well, is the drugs acting on the nervous system. Although the percentage of chiral compounds can only be assessed moderately high, it is certainly remarkable that no subclass of 0% chirality exists here. These findings seem to support the assumption that, as a rule of thumb, the subtler the biological effect, the more likely the specific (chiral) binding. This is characteristic of the CNS, but the relationship is stochastic, at best.

Table 2 Chiral statistics of bioactive molecules Pharmacological class

Number of subclasses

Total number of compounds

Number of chiral compounds

% of chiral compounds

Alimentary tract and metabolism

15

321

166

51.7

Antiinfectives Antiinflammatory Antineoplastic and immunmodulating Antiparasitic, insecticides, repellants Blood and blood forming organs

8 5 3 10 6

720 392 368 241 133

371 177 221 77 57

51.5 45.1 60.0 31.9 42.8

Cardiovascular system Dermatologicals Hormonal system Musculo-skeletal system Nervous system Respiratory system Various Narcotic drugs

20 7 12 9 23 6 6 0

727 158 254 149 1211 176 87 111

442 13 224 64 581 108 27 84

60.7 22.4 88.1 42.9 48.0 61.3 31.0 75.6

Psychotropic substances

4

116

69

59.5

The most chiral compound Name

% of chiral carbons

Sucralfate Lactulose Kanamycin Halometasone Mitobrontil Paromomycin Pentosane polysulfate sodium Isosorbide Cystine Diflucortolone Aurothioglucose Chloralose Glycerol, iodinated Ioglucomide Morphine-Noxide Normorphine Fencamfamine

75 75 83.3 40.9 66.7 82.6 82.6 66.7 33.3 40.9 42.9 75.0 50.0 40.0 31.25 31.25 26.6

352

Table 3 Pharmacological subclasses containing high % of chiral compounds Pharmacological class

Pharmacological subclass

Alimentary tract and metabolism Antiinfectives Antiinflammatory Cardiovascular system

Anabolic Anorexic Antirickettsial Prostaglandins Aldosterone antagonist Antiadrenergic Ca2+channel blocker Androgen Antiandrogen Estrogen Glucocorticoid Luteolytic Oxytocic Progestin Postatic growth inhibitor Antimigraine Antiparkinsonian Dopamine agonist MAO inhibitor Narcotic antagonist Bronchodilator Expectorant Narcotic drugs "Schedule I"

Hormonal system

Nervous system

Respiratory system Narcotic drugs Psychotropics

Total Number of number of chiral compounds compounds

% of chiral compounds

29 35 5 9 7 56 6 27 9 35 89 4 11 52 1

28 31 4 9 7 56 6 27 7 27 89 4 10 52 1

96.5 88,5 80.0 100.0 100.0 100.0 100.0 100.0 78.0 77.0 100.0 100.0 91.0 100.0 100.0

11 33 12 5 18 65 11 111 32

9 25 11 4 16 48 8 84 24

82.0 76.0 92.0 80.0 89.0 74.0 73.0 76.0 75.0

The "most chiral" compounds (and percentage of their chiral carbons) are: kanamycin (83.3%), (Fig. 2). aurothioglucose (83%), paromomycine (82.6%), pentosane-polysulfate-sodium (80%). The "most chiral" drug molecules, not surprisingly, are sugar-type compounds, produced by fermentation in "biological laboratories" of fungi or bacteria, clearly, under strictly chiral biochemical circumstances. The statistics above allows to draw the conclusion that chirality, as a general, possible feature of a present day drug molecule is more likely to be a consequence of its origin than a prerequisite of its biological action or receptor-fitting. Perfect, complementarily fitting ligand-receptor interaction can take place by the participation, for example, of a chiral receptor surface, and a prochiral guest molecule. Due to the requirement of highly specific drug action, however, the long-term

353

tendency is certainly the increase of chiral compounds in the pool of drug molecules, and their chirality will be more characteristic of the biological target molecule, than the origin of the drug.

Exogenous compounds and their endogenous ligands. Structural similarities and superimposable moieties. Chiral genetics of narcotic and psychotropic compounds An important classification criterion of exogenous, narcotic and psychotropic compounds is the extent of dependence or addiction that can develop. Table 4 enlists those compounds or compound families that are usually considered minor in their abuse propensity. Minor abuse drug molecules are at most, moderately chiral. Barbiturates, benzodiazepines are only chiral, if R1 and R2 are not equal, and R2 = hydrogen, respectively. These criteria are rather the exceptions than the cases. Alcohol is not at all considered to be chiral. Nevertheless, this compound nicely exemplifies the recent paradigm that everything is chiral, and the observation of chirality is only a matter of resolution [16]. For example, in ethyl-alcohol, if one of the methylene hydrogens is an isotope of hydrogen (deuterium or tritium), the compound is obviously chiral. The same is true, if deuterium and tritium substitutes two hydrogens of the methyl moiety. In the class of minor abuse compounds, nicotine is the only clear-cut asymmetric one. Caffeine and organic solvents and most anaesthetics are not chiral compounds. The so-called "prescribing drugs" category is a miscellaneous one; their addiction power is closely related to the highly individual "relationship" between the user, and the drug in question. The major abuse drugs, the addiction strength, the percentage carbon chirality, and their source are enlisted in Table 5. The rightmost column in Table 5 indicates the origin of the drug. Many of the abuse drugs in these classes are, however, semisynthetic derivatives, with modified effect, side effect, duration or toxicity. The data in Table 5 and pharmacological properties show that a typical narcotic/psychotropic drug: (a) is produced in plants; (b) contains a significant % of chiral atoms; (c) has a strong effect on CNS, related to neurotransmitter functions. Rationale predicts that if such a drug has some benevolent effect as well, it probably has an endogenous ligand, which, under non-pathological circumstances, contributes to the homeostasis of the body. An endogenous ligand, as a matter-of-course, is produced in the body, binds the same receptor, and has a very similar effect. The hypothetical relationship between exogenous and endogenous ligands generates a few further assumptions. Since both narcotic drugs and their endogenous ligands are natural compounds: (a) they might have a common origin; (b) they might be chirally related; (c) their receptor-binding moieties might be superimposable. The above hypotheses can be substantiated or denied by investigating the exogenous-endogenous ligand relationships one by one, as follows:

354

Table 4 Minor abuse/narcotic drugs Name

Example

Dependence / addiction

Barbiturates

o R1 RU~/'NH

strong

0/'~ N-'~.... ./~N-~ "--R2

Benzodiazepines

X"

~R3

medium

Alcohol

C H 3 - - C H 2 -- O H

strong

Nicotine

~ N

strong O

Caffeine

CH3

H3C"NJ~ N

o ~-.N.----N

weak

CH3CH3 i

1

Organic solvents

,.~

strong

Anaesthetics

N2

medium

"Prescribing" drugs

scopolamine, ephedrine, various anabolics, antihistamines, etc.

1.

2.

Cocaine is a narcotic drug, for which no real endogenous ligand is believed to exist. Its action takes place on adrenergic and dopaminergic receptors. It is difficult to find, however, real resemblance between the cocaine, norepinephrine and dopamine structures (Fig. 3). The molecular mechanism of the local anaesthetic activity of cocaine is even less known. For tetrahydrocannabinol, the endogenous ligand has been claimed to be anandamide [17] (Fig. 4). Clearly, the structure, and apparently all chemical properties of tetrahydrocannabinol and anandamide are very dissimilar. The structural chemist has therefore serious doubts that these compounds can possibly fit specifically into the same receptor-pocket.

355

CH2NH2

NH2

HO, .r~,~O

A j .-

HO

HO, '""O,.

o. ~

,OH

O .....

6H H2N, a'~,'~.~'.',',N~H Kanamycin Fig. 2. Kanamycine, the "most chiral" drug molecule.

Exogenous compound

Endogenous compound Noradrenalin

Cocaine H3C.

HO

COOCH 3

N

oocO H

HO

OH

c~ Dopamine

NH2

NH2

f

)

OH Fig. 3. The structure of cocaine, noradrenaline and dopamine. Table 5 Major abuse drugs Name of drug or drug family

Examples

Dependence Addiction

% chirality

Source

Opiates

Morphine

very strong

29

Cocaine Cannabinoids Psychedelics Amphetamines

Cocaine THC LSD Amphetamine MDA, MDMA

very strong weak or no weak or no strong

24 9 10 11

Papaver somniferum Erythroxylon coca Cannabis sativa Secale cornutum Ephedra distachia

356

Exogenous compound A9 Tetrahydrocannabinol

Endogenous compound Anandamide

CH 3 0

OH

~

OH

H, H3C/ -C

CsH11

Fig. 4. The structure of tetrahydrocannabinol and anandamide.

3.

4.

Amphetamine, and its psychomotor stimulant or psychedelic phenyl-ethylamine derivatives, such as 3,4-methylenedioxy-amphetamine (MDA) and 3,4-methylenedioxy-methamphetamine (MDMA), are active principles in several so-called DISCO drugs. The central sympathomimetic activity is related to the chemical resemblance with fundamental neurotransmitters, norepinephrine and 3,4-dihydroxy-phenylalanine (DOPA). Bioavailability and the enhanced central (over peripheral) activity are due to the higher lipophilicity and the concomitant better ability to cross the blood-brain barrier. Fig. 5 shows the stereospecific structures of the exogenous and endogenous compounds. Formal chirality between amphetamine, MDA and MDMA vs R(-)norepinephrine is quite meaningless, since the chiral centres (carbon atoms) are located differently in the exogenous compounds and in norepinephrine. The analogous comparison with S(-)DOPA, the parent compound, results in apparently identical, S-configuration, which is due to the reduction of carboxylate into methyl group, and also, the conversion between two of the three other substituents on the chiral carbon. Concerning a comparison between amphetamine, MDA, MDMA and dopamine, the latter one is achiral, (or prochiral), a real configurational relationship is therefore irrelevant. The infamous psychedelic compound, lysergic acid diethylamide (LSD) provides an enhanced perception of sensory stimuli, in a so-called mind-expanding way. These perceptions of the central nervous system (CNS) can be well explained at the molecular level by the double mimic properties of LSD, since both indolethylamine (5-HT, serotonine)-type, and a phenyl-ethyl-amine (dopamine, DA)-type moieties (Fig. 6) are covalently embedded in the LSD molecule. Since both 5-HT and DA are pro-chiral compounds, comparisons could only be made between LSD, and the "chiral conformations" of these neurotransmitters.

357

Endogenous compound

Exogenous compound

R (-) norepinephrine

S (+) amphetamine

HO

H ~CH2~NH2

NO

CH3

N NN2

S (+) MDA S (-)DOPA

H

HO L O

OH3 S (+) MDMA

+ NH3 COO

H

O ~ - ~ ~ - - CH2---~ ~0

~CH3

CH3

Fig. 5. The structure of amphetamine, MDA, MDMA, norepinephrine and DOPA.

.

Morphine, the first purely isolated alkaloid (Sertiirner, 1806), possesses at least 6 different types of biological activity (analgesic, respiratory depressant, soporific, cough-depressant, constipating, euphorizing). Its endogenous ligands, (the endogenous opiates, endorphines enkephalines) were only discovered in the mid-1970s [18]. The structure of morphine and Met-enkephaline, one of the endogenous opiates can be seen in Fig. 7. Morphine is a fused, pentacyclic, rigid ring-system alkaloid, whereas Met-enkephaline and the related other endorphins and dinorphins are flexible peptides. At first glance, apparently, there is hardly any chemical similarity between these groups of compounds. Although endogenous opiates vary in length of chain and composition, they are invariant in their N-terminus, which is tyrosine. Thus, a closer look at morphine and any of the endogenous opiate molecules reveals that they all have a set of common moieties: phenolic hydroxyl, aromatic ring, methylene group, methine group (with a chiral carbon) and a basic nitrogen. This locus can certainly fit the complementary receptor surface, initiating the reaction cascade, resulting in a highly similar biological activity. An interesting structural aspect of these corresponding compounds is the configuration of the analogous methine carbon atom. The Cahn-IngoldPrelog convention shows R-configuration for the morphine- and S-configuration for the tyrosyl-methine carbon. Despite this apparent

358

Exogenous compound

Endogenous compound

(+)-5R-LSD

Serotonine (5-HT)

O

NH2

C2H5\N H , ~ . T / ~ C2H5.,/ " N~CH3 H

HO..

(indolethylamine) Dopamine NH 2

iS OH (phenylethylamine) Fig. 6. The structure of LSD, 5-HT (serotonine), and dopamine (DA).

Exogenous compound

Endogenous compound

Morphine

Tyrosine

,o

..CH 3

" O O C / C H " - NH+

HO Met-enkephaline OH

CH2

, tCH2)2 CH +H3N.~CH..COI~HCONI~CONH/ "CONH"CH CO(~ Tyr - Gly - Gly - Phe Met Fig. 7. The structure of morphine and met-enkephaline.

359 contradiction, a three-dimensional analysis clearly indicates that the common moieties are perfectly superimposable, supporting the evidence of analogous binding. The three- (or more)-point, enantiomer-specific binding mode is proven by the fact that the distomeric antipode of morphine is inactive, and the truncated derivatives all have a significantly reduced activity. It is certainly remarkable that moiety-superimposion and the analogous three-point binding mode can be fully achieved by peptides of tyrosine C-terminus with opposite (formal) configuration, but impossible to achieve by the optical antipode of morphine. These facts indicate the very different significance of configurational properties in rigid and flexible molecules. Concerning the molecular genesis of morphine and endogenous opiates, biosynthetic studies indicate the plausible hypothesis that both compounds can be traced back to tyrosine. In the biosynthesis of morphine, tyrosine is condensed with dopamine, the decarboxylated derivative of dihydroxyphenylalanine, resulting in a rank-number conversion at the chiral centre [19]. No such conversion takes place in peptide synthesis-type reactions. Thus, despite the identical parent compounds, the formal configuration of the analogous methine carbons is R in morphine, but S in tyrosine and the related endogenous opiates. This fact does not make any difference in their suitability in specific receptor reactions.

Resumd

The most important observations, tendencies and statements on chirality of drugs and related compounds can be summarized as follows: 1. The number of chiral drug molecules is currently steadily increasing. 2. Drugs that have been used as recemates are in many cases redeveloped and marketed by the manufacturers as single enantiomers (racemic switch). 3. Presently, the percentage of chirality in drug classes is more characteristic of their origin than the target molecule. 4. Even though formal chirality of exogenous and endogenous ligands is different, they can be genetically and stereochemically related, as seen by the example of morphine and endogenous opiates. 5. Conventional chiral descriptors (Fischer's projection, D/L, R/S conventions) may fail to characterise real, 3D similarities (e.g. morphine and opiates). 6. Some compounds that have been claimed on a pharmacological basis to be endogenous ligands are certainly questionable on a stereochemical basis (tetrahydrocannabinol and anandamide). 7. Unequivocal judgements on binding analogies can be done when molecular details on the ligand-receptor interaction have been elucidated by nuclear magnetic resonance or other powerful structure-elucidating techniques.

360

References [1] S. Fabro, R.L. Smith, R.T. Williams, Nature, 215 (1967) 296. [2] N.T. Johansen, B. Ebert, H. Brauner-Osborne, M. Didriksen, I.T. Christensen, K.K. Soby, U. Madse, P. Krogsgaard-Larsen, L. Brehm, J. Med. Chem., 41 (1998) 930-939. [3] M. Simonyi, G. Maksay, Stereochemical aspects of drugs II. In: The Practice of Medicinal Chemistry, C.G. Wermuth (Ed.), London, 1996, p. 420. [4] C.C. Pfeiffer, Sciences, 124 (1956) 29-31. [5] M. Simonyi, Medicinal Research Reviews, 4(3) (1984) 359-413. [6] M. Simonyi, Enantiomer, 1 (1996) 403-414. [71 M. Simonyi, Advances in Drug Research, 30 (1997) 75-110. [81 A. Karim, A. Piergies, Clin Pharm. and Therapeutics, 58 (1995) 174 [91 E.I. Isaacson, Methylxanthines. In: Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, J.N. Delgado, W.A. Remers (Eds.), 1992, p. 398. [lo] E.P. Hanna, Sympathomimetic agents. In: Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, N.J. Delgado, W.A. Remers (Eds.), 1992, pp. 424-425. [11] A.R. Fassihi, Int. J. Pharmaceutics, 92 (1993) 1-14. [12] G. Frater, J.A. Bajgrowicz, P. Kraft, Tetrahedron, 54(27) (1998) 7633-7703. [13] S.C. Stinson, Chemical and Engineering News, 21 (1998) 83-104. [14] C.J. Drayton, Drug Compendium (Vol. 6). In: Comprehensive Medicinal Chemistry, C. Hansch (Ed.) Oxford, 1990, pp. 242-965. [15] International Narcotics Control Board's List (Vienna), 39th Edition for Narcotic Drugs, 1997, 18th Edition for Psychotropic Substances, 1997. [161 P.G. Mezey, Theory of biological homochirality: chirality, symmetry deficiency and electron-cloud holography in the shape analysis of biomolecules, abstracts of papers Symposium on Biological Homochirality, Serramazzoni, Italy, Sept. 6-12, 1998. [17] W.A. Devane, L. Hanus, A. Breuer, R.G. Pertwee, L.A. Stevenson, G. Griffin, D. Gibson, A. Mandelbaum, A. Etinger, R. Mechoulam, Science, 258 (1992) 1946. [18] A. S. Horn, J.R. Rodgers, Nature, 260 (1976) 795. [19] A.R. Battersby, J.A. Martin, E. Brochmann-Hanse, J. Chem Soc., (1967) 1785.