Stereoselectivity at muscarinic receptor subtypes: observations with the enantiomers of phenglutarimide

Abstract

The affinity of the enantiomers of phenglutarimide at three muscarinic receptor subtypes was examined in vitro using field-stimulated rabbit vas deferens (M1 receptors) and guinea pig atria (M2 alpha receptors) and ileum (M2 beta receptors). Extremely high stereoselectivity was observed and higher affinities (up to 6000-fold) were found for the (+)-S-enantiomer. The stereoselectivity ratios were different at the three subtypes, and the stereochemical demands made by the muscarinic receptors were most stringent at M1 receptors. (+)-(S)-Phenglutarimide was found to be a potent M1-selective antagonist (pA2 at M1 = 8.53). Its receptor selectivity profile is qualitatively similar to that of pirenzepine. (-)-(R)-Phenglutarimide showed no comparable discriminatory properties.

Stereoselective inhibition of muscarinic receptor subtypes by the enantiomers of hexahydro‐difenidol and acetylenic analogues

“…In the last few years, data have accumulated that muscarinic receptors can be differentiated on the basis of their stereoselectivity to chiral antagonists such as procyclidine Tacke et al, 1986;Waelbroeck et al, 1988b), trihexyphenidyl 1989d), phenglutarimide (Lambrecht et al, 1989a), biperiden (Eltze & Figala, 1988) and telenzepine (Eveleigh et al, 1989). Hexahydro-difenidol (1) and its analogues hexbutinol (2), hexbutinol methiodide (3) and p-fluoro-hexbutinol (4) ( Figure 1) possess a centre of chirality and therefore exist in two enantiomers.…”

Stereoselective recognition of the enantiomers of phenglutarimide and of six related compounds by four muscarinic receptor subtypes

“…This is due to the fact that the drugs had low affinities for the [3H]-NMS- (1.07 ± 0.09) pA2 values and slopes of Schild plots (in parentheses) are presented as means + s.e.mean (N= 3 -6). (a)Data taken from Lambrecht et al (1989a). (b)Only two antagonist concentrations were investigated.…”

“…In contrast, the identity of the prejunctional inhibitory heteroreceptor in the rabbit vas deferens is still controversial (see Introduction). Since we had previously observed that (S)-phenglutarimide [(S)-1] but not (R)-phenglutarimide [(R)-1] could discriminate the M1/ M4 inhibitory receptors of the rabbit vas deferens from the M2 and M3 receptors (Lambrecht et al, 1989a), we decided (Tables 1 and 2) were very similar to the corresponding antimuscarinic potencies (pA2 values), summarized in Table 3. The most selective compound on native and cloned muscarinic receptors was (R)-thienglutarimide ((R)-2), with a 7 to 100 fold preference for ml (M1) receptors over the other three subtypes.…”

“…a lower affinity Waelbroeck et al., We were able to identify, in binding studies, four native 1989;1992;Feifel et al, 1990;. In functional muscarinic receptors with different selective antagonists bindstudies, the enantiomers of the antiparkinsonian drug, ing profiles in rat tissues and in NB-OK-I cells (Waelbroeck et phenglutarimide (Lambrecht et al, 1989a) have been shown al., 1990b). The binding properties of these four receptor to display an extremely high stereoselectivity (up to 6000 subtypes correlated with, respectively, the binding profile of fold) at muscarinic receptors.…”

“…We had previously observed that, in functional studies, the eutomer (S)-phenglutarimide is able to discriminate the inhibitory receptors in the rabbit vas deferens from the M2 and M3 receptors in heart and ileum, respectively, whereas the distomer (R)-phenglutarimide is non-selective (Lambrecht et al, 1989a). We therefore hoped that a study of the binding properties of these and related compounds might help us to identify the prejunctional, inhibitory rabbit vas deferens muscarinic receptor subtype unambiguously.…”