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When this compound was analysed it was found to be no longer a quinazoline, but to have undergone a novel ring enlargement to become a 7-membered 1,4 benzodiazepine V. It was, in fact, chlordiazepoxide.

O'"~~N~..I~ 0 (b) V Roche then degraded the molecule and found to their surprise that neither the methylamino group (a) nor the N-oxide grouping (h) were essential, and the next successful member (diazepam) lacked both

of these moieties. By testing a further 2 000 compounds, each of which was tested for 20 to 50 biological activities, further variants were developed. Here then is an example of intuition, persistence, and the choice of an appropriate system for study. Further articles in this series will examine the discovery of ~adrenoreceptor blocking agents and the H~-receptor antagonists, the butyrophenones and review the work of Hitchings in nucleic acid metabolism. Any selection is invidious, but these examples have been chosen to give substance to the elements of creativity, outlined earlier.

Acknowledgements These articles could not have been written without the help of the scientists them-

selves, and I acknowledge my debt to them: Dr Roth and Dr Stembach of Roche, Prof. Jenny of CibivGeigy, Dr Doyle of ICI, Dr Duncan of Smith Kline and French, Dr Jansscn of Janssen, Sir James Black, Dr Vane and Dr Hitchings of Burroughs Wellcome. JULIANH. SHELLEY Boehringdr lngelhem, Southern Industrial Estate, Bracknell, BerkshireRG12 4YS, U.K.

Reading Vlst 1 Krebs, H

A. and Shelley, J

H . ( 1 9 7 5 ) ill T h e

Creative Process m Science and Medicine,

ExcerptaMedica, Amsterdam 2 Dorfman, L., Furlenmctcr, A., Huebncr, C. F, Lucas, R., MacPhillamy, H. B., Mueller,J. M., Schhttler, E., Schwayzer,R. and St. Andre, A. F. (1954) Heir. Chun. Acta 37, 59-75 3 Woodward,R. B , Badcr, F. E., Bickel,H., Frey, A J. and KJerstead,R W. (1956)J. Am. Chem. Soc. 78, 2023--2025

o8 ic Stereochemistry and biological activity of drugs International Symposium, held on the 21 and 22 October 1 982 in Noordwijkerhout, The Netherlands.

Most enzymes and receptors show metric molecules with one enantiomer in stereoselectivity in their recognition of, and excess is, in principle, not a problem. The interaction with, their substrates and problem is to bring about a production rate endogenous ligands. Medicinal chemistry of one enantiomer larger than the correshas created many drugs with one or more ponding racemization rate. asymmetric centres. Drugs with chiral Ari6ns (Nijmegen) elucidated and discentres, or those possessing cis/trans iso- cussed various aspects of stereoselectivity merism, are frequently marketed as race- in bioactivity, such as its dependence on the location of the centre of asymmetry, tbe mates or mixtures of c/s- and transisomers. Since nature confronts us with action of agonists v. that of competitive stereoselectivity, interesting problems may antagonists and differences in affinityand arise, such as the relationship between intrinsic activity based on differences in stereoselectivity and drug activity, or the stericstructure.The more activemember of advantages or disadvantages of the clinical a pair of isomers is referred to as tlm use of racemates, rather than the phar- eutomcr, the less active isomer as the distomcr and the ratio of the activitiesof macologically active enantiomer. The aim of the organizing committee was eutomer and distomer is termed the to bring together medicinal chemists, eudismic ratio. There appears to he a pharmacologists, pharmacists and clini- remarkable relationship between the cians for a 2-day, multidisciplinary discus- eudismic ratio and the activity of the sion of various topics in the fields of cutomcr in various series or families of stereochemistry and biological activity of related compounds. The eudismic ratio is drugs. To my knowledge, this congress is positively correlated with the activity (pI~, one of the few symposia devoted entirely to pA2, EDso) of the eutomer in the pair of stereochemistry as it relates to drug activ- isomers. In his own characteristic way, ity. The presentations on the first day dealt Ari6ns defended the suggestion that the with introductory aspects to define the presence of a non-active, but possibly topic, and were chaired by van Ree dangerous, enantiomer in a racemate is pure waste and an unnecessary burden on (Utrecht). The origin and basis of stereoselectivity the environment and biological system. For in biology was discussed by Rauws example, the use of I 000 kg of a racemic (Utrecht). The selection of asymmetric weedkiller or insecticide implies the building blocks of enzymes took place in unnecessary pollution of the environment the prebiotic phase of evolution, before the with 500 kg of a xenobiotic substance. Stereoselectivity and drug metabolism origin of life. The abiotic origin of asym-

were discussed by Vermeulen (Leiden). Stereochemical factors play a significant role in the metabolism of drugs and other xenobiotics. This originates from the interaction of chiral drugs with the drug metabolizing enzyme(s), such as mixed function oxidases, epoxide hydrolases and ghitathione transferases. Different rates of metabolism and formation of different products have been observed. Complete stereoselectivity in drug metabolism is a rare phenomenon. Stereoselectivity and pharmacon distribution was the topic discussed by van Ginneken (Nijmegen). Stereoselective distribution may occur as soon as carrier transport is involved (e.g. in the intestine or kidney). Isomers may have different transport characteristics, but substantial stereoselectivity is the exception rather than the rule. On the other hand, the stereoselective neuronal (re)uptake of transmitters and drugs has been welLdocumented. Therapeutic implications may be that the less suitable, and possibly less potent, isomer inhibits the transport of the other, thereby reducing its action. Mutschler (Frankfurt) used cyclic, conformationally constrained, rigid, or semirigid, analogues of flexible drug molecules to investigate the participation of conformational isomerism in drug activity/selectivity. He discussed using analogues of acetylcholine to analyse conformation-selectivity relationships of muscarinic and nicotinic receptors by this approach. The stereochemistry of binding to receptors was considered by Burgen (London). NMR studies of stereoisomeric pairs bound to receptors show that part of the ligand may bind in the same way in both isomers,

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286 whereas other parts of the ligand may be prevented from binding at all. Substitutions may lead to major reorientations of binding with increased or decreased affinity. In the general discussion following these presentations attention was mainly focused on the postulate formulated by Arifins as to whether the application ofracemates in preference to the active isomer is justified. There seemed to be general agreement that, whenever possible, only the pharmacologically-active enantiomer of a drug should be used, rather than the racemic mixture, in order to eliminate an unnecessary burden on the organism. Only if resolution is impossible and no other (non-optically active) drug is available, can the application of racemates be accepted. However, if the biologically inactive, or less active, isomer does not cause any harm, there is little reason to resolve the racemate as this will only raise the price of the drug. The next session, chaired by van Rijn (Amsterdam), consisted of a presentation by Soudijn (Amsterdam) which continued the discussion on the advantages and disadvantages of the application of bioactive racemates or specific isomers as drugs. With appropriate examples he showed that the eutomer should be used in clinical practice in case the distomer contributes to side-effects, counteracts the pharmacological action of the eutomer, or is metabolized to pharmacologically undesirable or toxic products. On the other hand, racemates can, and should, be used when racemate and eutomer are equipotent and equitoxic or when the racemate is more active than both intrinsically equipotent isomers, and when enzymic inversion of the distomer occurs. In the discussion which followed the general feeling was once again that the decision whether to use the racemate or the active enantiomer must be decided on an individual basis for each drug. Most participants felt it prudent to use only the most clinically active enantiomer whenever possible. In doing so, the possibility of sideeffects and toxicities which may result from the less active (or inactive) enantiomer would be reduced. In the case where a racemate combines an agonist with an antagonist, the mixture will often behave as a partial agonist in the initial screening tests. This was considered a risk in the discovery of new drugs, but is inevitable, since the resolution of each product would be too costly. The first session on the second day, chaired by Ari6ns (Nijmegen), was devoted to more specific examples illustrating the principle of stereochemistry in drug activity and selectivity. Ruffolo (Indianapolis) discussed almost everything that is known at present about the

T I P S - J u l y 1983

stereoselectivity of adrenergic drugs. His own work showed that the Eassorv-Stedman hypothesis, i.e. R(--) > S(+) = fl-desoxy, is valid for phenylethylamines interacting with all adrenergic receptor subtypes, i.e. al, a2,/31 and f12, but does not hold for the imidazol(id)ines. For phenylethylamines with 2 asymmetric centres activity resides in the 1R,2S(--)erythro form. fl-Adrenoceptor antagonists have stereochemical requirements similar to those of the agonists. Competitive a-adrenoceptor blocking drugs display little or no stereoselectivity, the benzodioxane class excepted. Most irreversible a-adrenergic blocking agents also show no stereoselectivity. A lecture on stereoselectivity in cholinergic agonists and antagonists was presented by Dahlbom (Uppsala). Attention was given to acetylcholine and its congeners, as well as to conformationallyrestricted analogues of this neurotransmitter, muscarine, muscarone and dioxolanes. Antagonists were also considered. A detailed discussion was offered on the question of whether all agonists occupy the same binding site, whether agonists and antagonists identify the same binding site and at which positions a chiral centre affected stereoselectivity. The next speaker, Bogaert (Gent), discussed the stereoselectivity of dopaminergic and antidopaminergic agents. The flexibility of the neurotransmitter dopamine probably explains the fact that its effects are mediated by various receptor types. He also discussed the classification of dopamine receptors, which is a matter of debate at present. Dopamine agonists, as well as dopamine antagonists, show stereoselectivity for different classes of dopamine receptors. This may help to obtain more detailed information on the different subtypes of dopamine receptors both in the CNS and in the periphery. Stereoselectivity in peptides was illusgated by Witter (Utrecht). The replacement of the naturally occurring L-amino acids in peptides by D-amino acids results in conformational changes influencing biological activity and in a generally improved resistance against enzymatic attack. For example, in ACTH neuropeptides, D-amino acid substitutions increase potency and duration of action, and shift behavioral activity profiles. In vasopressin, D-amino acid substitutions can increase specificity by preferentially decreasing the vasopressor: antidiuretic ratio. The impact of stereochemistry on the selectivity and pharmacological profile of biologically active molecules was presented by Timmermans (Amsterdam), with examples from various drug fields. The examples were chosen to cover a wide

range of biological responses, with diuretics, antimalarial drugs, calcium antagonists, hypnotics, GABAergic, hypotensive and antidepressant drugs, used to demonstrate the role of stereochemistry in drug selectivity. The final presentation of the symposium on clinical use of racemates or specific isomers was given by Rahn (Maastricht). He stressed that there are now numerous drugs in clinical use of which the therapeutic effect resides in one isomer. For example, fl-adrenergic blockade is governed by the L-isomer of fl-adrenoceptor antagonists. Both enantiomers, however, possess membrane stabilizing activity. Clinical studies show no increase of frequency and severity of side effects due to the presence of the D-form of fl-blockers. This perhaps justifies the general use of racemates in this particular drug class. The symposium ended on a discussion of the clinical utility of racemates or individual enantiomers. In this respect 2 interesting drugs show that in some cases the racemate is to be preferred to the most active isomer because both enantiomers are required for the overall clinical effect of the drug. Labetalol is known as a drug possessing al- and fl-adrenergic blocking activities. In reality, labetalol is a mixture of 4 isomers, since the molecule contains 2 asymmetric centres. Only one isomer is responsible for the al-adrenoceptor blocking effect, whereas the fl-blocking activity resides in another isomer; so, 50% of labetalol is biologically inactive. With dobutamine it has been observed that the (-)-isomer is predominantly an a-adrenergic agonist, while the (+)enantiomer has preference for stimulating fl-adrenoceptors. The problem of radioracemization was also briefly touched. This seems to be a rather unexplored area. It cannot be simply circumvented and poses serious problems in preparing radiolabeled optical isomers. To summarize, the symposium in Noordwijkerhout offered an interesting blend of basic and clinical research on drugs possessing asymmetric centres.

Acknowledgements The symposium was organized by the Dutch Society of Pharmacology, the Medicinal Chemistry Section of the Royal Dutch Chemical Society, and the Dutch Society of Clinical Pharmacology and Biopharmacy. Financial support and secretarial help was donated by Hoechst Pharma, the pharmaceutical division of Hoechst Holland N.V. P. B. M. W. M. TIMMERMANS Department of Pharmacy, Division of Pharmacotherapy, Universtty of Amsterdam, Plantage Muidergracht 24, 1018 TV Amsterdam, The Netherlands.