Synthetic Analgesics: Stereochemical Considerations

Abstract

IN a review article1 in 1952 on "Analgesics," one of the present authors stated "it appears probable from a consideration of the diverse types of compounds which have an analgesic activity equal to, or greater than, that of pethidine, that the minimum requirement for activity may be a hydrophobic group (or collection of groups) containing a basic centre with an overall optimum spatial arrangement." Further "it is possible that the stereochemical configuration of the drug must be complementary to that of a certain tissue surface or enzyme system." Since the appearance of this article, much evidence has been forthcoming supporting the above statements. The purpose of this paper is to correlate the relevant information, to present stereochemical evidence obtained in our own laboratories, and to postulate the type of drug-receptor mechanism involved and the nature of the receptor surface.The importance of the spatial configuration in analgesics is most clearly demonstrated in those compounds possessing one asymmetric carbon atom. In all cases where optical enantiomorphs have been prepared and tested, one is always more active than the other of each pair, and, in many cases, the whole of the activity of the racemic mixture resides in one of the isomers. In Table I the analgesic activities of a number of en-antiomorphic pairs and the nature of their rotations are presented.The significance of the difference in activities of optical isomers in drug-receptor mechanisms only becomes established when the configurations of the isomers are elucidated. We have determined the configurations of a number of these optical isomers, some of varying chemical types ; the more analgesically active isomers of each enantiomorphic pair have identical spatial configurations which are related to that of D-(-)-alanine (see Fig. 1). (Figure 2 shows the outline of the reactions used in establishing the configurational relationships ; full chemical details will be published elsewhere.)The difference in biological activity exhibited by isomers of enantiomorphic pairs can be attributed to one or more of the following factors :1. difference in their distribution ; 2. difference in their rates of metabolism ; 3. preferential adsorption of one of the isomers by an optically active 4. difference in their ease of adsorption upon a complementary recep-5. difference in the nature of the drug receptor combination.constituent in the body before it can reach the site of action; tor surface ; 986

The Effect of Analgesic Drugs on the Release of Acetylcholine From Electrically Stimulated Guinea‐pig Ileum

“…Furthermore, the contractions could also be abolished by anoxia or by lowering the temperature to 270 C. Thus it is unlikely that the muscle was being stimulated directly. Beckett & Casy (1954) suggested that morphine-like drugs combined with specific receptors in the central nervous system to elicit an analgesic response. If the action of analgesic drugs on the stimulated ileum is also mediated through a combination with specific receptors, the structural requirements for inhibitory activity should resemble those for analgesia.…”

“…Analgesic activity resides in only one isomer of pairs of optical enantiomorphs of morphine-like drugs (Beckett & Casy, 1954). The effects of optical stereoisomers of analgesic drugs have been compared on the responses of guinea-pig ileum to electrical stimulation.…”

Propionic acid 1,2-dimethyl-3-phenyl-3-pyrrolidynyl ester hydrochloride: prodilidine

“…group relative to the piperidine or pyrrolidine rings contradicts the receptor theory of Beckett & Casy (1954).…”

Molecular structure of opiate alkaloids. III. Crystal structure of two 7-(1-cyclohexylethyl)oripavine analogues

“…Beckett & Casy (1954) proposed a model based on the assumption that the association of a drug on the receptor site involved three specific subsites: an anionic center to interact with the N atom, a hydrophobic site where the aromatic ring lies and a 'hole' to accommodate C15 and C16. In a recent article we reported the conformational properties of two 16-alkyl analogues of thebaine and oripavine: compounds (III) and (IV) (Fig.…”