The design and pharmacology of novel selective muscarinic agonists and antagonists

Characterization of the muscarinic receptor subtype(s) mediating contraction of the guinea‐pig lung strip and inhibition of acetylcholine release in the guinea‐pig trachea with the selective muscarinic receptor antagonist tripitramine

“…This pattern is reminiscent of that obtained with the M 2 selective muscarinic antagonists previously tested, i.e. gallamine, methoctramine, AF-DX 116 and AQ-RA 741 (Roel et al, 1993), which, like tripitramine in the present study, exhibited slightly lower anities at guinea-pig lung strip than at cardiac Buckley et al, 1989;DoÈ rje et al, 1991;Doods et al, 1993;Lazareno & Birdsall, 1993;Maggio et al, 1994;Kilbinger et al, 1995;Lambrecht et al, 1995;BraÈ uner-Osborne & Brann, 1996). Note that the correlation coecients given in the Figure regard the best ®tting line through the data points, not the line of identity.…”

“…From the p K B value of 8.76, the subtype of muscarinic receptor mediating contraction of the guinea‐pig lung strip appears rather atypical. Thus, this p K B value is lower than the affinities observed at M 2 receptors in guinea‐pig and rat atria (9.37–9.60, this study; 9.14–9.85, Melchiorre et al , 1995; Chiarini et al , 1995) and at M 2 receptors in rabbit vas deferens and anococcygeus muscle (9.1, Lambrecht et al , 1995), but higher than those obtained at M 4 receptors (binding affinities obtained at native and cloned M 4 receptors being 7.93–8.19, Melchiorre et al , 1993; Maggio et al , 1994; functional affinity at M 4 receptors as found in rabbit anococcygeus muscle being 7.69, Lambrecht et al , 1995), and much higher than at M 3 receptors (affinities in guinea‐pig trachea and guinea‐pig and rat ileum being 6.1–6.8, this study and Chiarini et al , 1995). This pattern is reminiscent of that obtained with the M 2 selective muscarinic antagonists previously tested, i.e.…”

“… Correlation plots for the p K B values obtained with receptor antagonists at prejunctional muscarinic autoinhibitory receptors in guinea‐pig trachea and affinity estimates (p K B or p K i for these compounds towards (a) M 1 ; (b) M 2 , (c) M 3 and (d) M 4 muscarinic receptor subtypes, as compiled from the literature (Roffel et al , 1988; 1993; Buckley et al , 1989; Dörje et al , 1991; Doods et al , 1993; Lazareno & Birdsall, 1993; Maggio et al , 1994; Chiarini et al , 1995; Kilbinger et al , 1995; Lambrecht et al , 1995; Bräuner‐Osborne & Brann, 1996). Note that the correlation coefficients given in the Figure regard the best fitting line through the data points, not the line of identity.…”

“…In the present study, the new muscarinic receptor antagonist tripitramine, which has been shown to discriminate relatively well between M 2 and M 4 and very clearly between M 2 and M 3 muscarinic receptor subtypes (Melchiorre et al, 1993;1995;Lambrecht et al, 1995), was used in an attempt to identify unequivocally the receptor subtype(s) involved in this contractile response. From these experiments, the anity (pK B ) obtained for tripitramine in antagonizing muscarinic agonistinduced contraction of the guinea-pig lung strip was concluded to be 8.76, as calculated from the shifts obtained with tripitramine 10 ± 300 nM after 2 h of antagonist preincubation.…”

Identification of a series of CCK-2 receptor nonpeptide agonists: Sensitivity to stereochemistry and a receptor point mutation

“…At the ␣2A-adrenoreceptor, medetomidine enantiomers have been demonstrated to possess agonist and inverse agonist activity, respectively (22). In addition, among muscarinic receptor ligands, stereoisomers of compound BN225 have been reported to have agonist vs. antagonist function (23). Our results, taken together with the literature, suggest that among the enantiomers of known antagonists and related compounds are molecules with detectable intrinsic activity.…”