Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes

Abstract

In an attempt to assess the structural requirements of hexahydro-sila-difenidol for potency and selectivity, a series of analogues modified in the amino group and the phenyl ring were investigated for their affinity to muscarinic M 1 -(rabbit vas deferens), Mr (guinea-pig atria) and Mr (guinea-pig ileum) receptors. All compounds were competitive antagonists in the three tissues. Their affinities to the three muscarinic receptor subtypes differed by more than two orders of magnitude and the observed receptor selectivities were not associated with high affinity. The pyrrolidino and hexamethyleneimino analogues, compounds substituted in the phenylring with a methoxy group or a chlorine atom as weil as p-fluoro-hexahydro-difenidol displayed the same affinity profile as the parent compound, hexahydro-sila-difenidol: M 1 = M 3 > M 2 • A different selectivity patternwas observed for p-fluoro-hexahydro-sila-difenidol: M 3 > M 1 > M 2 • This compound exhibited its highest affinity for M 3 -receptors in guinea-pig ileum (pA 2 = 7.84), intermediate affinity for M 1 -receptors in rabbit vas deferens (pA 2 = 6.68) and lowest affinity for the Mrreceptors in guinea-pig atria (pA 2 = 6.01). This receptor selectivity profile of p-fluoro-hexahydro-sila-difenidol was confirmed in ganglia (M 1 ), atria (M 2 ) and ileum (M 3 ) of the rat. Furthermore, dose ratios obtained with either pirenzepine (Mt) or hexahydrosila-difenidol (M 2 and M 3 ) and the p-fluoro analogue used in combination suggested that the antagonism was additive, implying mutual competition with a single population of muscarinic receptor subtypes. These results indicate that p-fluoro-hexahydro-sila-difenidol represents a valuable tool for characterization of muscarinic receptor subtypes.

Nitric oxide‐dependent relaxation induced by M1 muscarinic receptor activation in the rat small intestine

“…This is in agreement with previous data indicating direct M 3 receptormediated intestinal smooth muscle contraction (Eglen et al, 1994). The rank order of potency of telenzepine on muscarinic receptors is M 1 4M 3 4M 2 (Eltze et al, 1993;Waelbroeck, 1992), and for p-F-HHSiD it is M 3 4M 1 4M 2 (Lambrecht et al, 1989). The chosen dose of telenzepine in this study has earlier been shown to successfully inhibit M 1 receptordependent nerve-induced NO-formation from intestinal tissue, without a ecting the M 3 receptor-dependent contractile response (Iversen et al, 1997).…”

“…In the presence of the selective muscarinic M 3 receptor antagonist p-F-HHSiD (Lambrecht et al, 1989) at 3610 77 M, the McN-A-343 (10 75 M)-induced relaxations were signi®-cantly enhanced to 38+4% of maximal relaxation (n=9, P50.05) (Figures 3 and 4). In addition, the increase in smooth muscle tone following the relaxation was inhibited by 82+10% by p-F-HHSiD at 3610 77 M, P50.001) ( Figure 3 The selective muscarinic M 1 receptor antagonist telenzepine (Eltze et al, 1985;Schudt et al, 1988) …”

Characterization of muscarinic receptors mediating relaxation and contraction in the rat iris dilator muscle

“…In Table 2, pA2 values for these antagonists determined in other studies in various preparations and shown in reviews by Hulme et al (1990) and by Caulfield (1993) and in an article by Lambrecht et al (1989) are also presented for comparison. It is clear that the pA2 values for these antagonists against pilocarpine-induced relaxation are close to those for M3 antagonism in other studies.…”

Characterization of muscarinic receptors mediating contractions of circular and longitudinal muscle of human isolated colon

“…In the published literature, atropine has been used as a non-selective high affinity antagonist at muscarinic receptors. Pirenzepine is a relatively high affinity antagonist for Ml muscarinic receptors with intermediate affinity for M4 muscarinic receptors and lower affinity for the M2 and M3 muscarinic receptors (Lambrecht et al, 1989;Caulfield & Brown, 1991;Dorje et al, 1991;Grimm et al, 1994). (11-[[[2 -(diethylamino)methyl] -l-piperidinyl]acetyl] -5,1 1-dihydro-6H-pyridol [2,3,-b][1,4]benzodiazepine-6-one) has high affinity for the M2 muscarinic receptor, but also has affinity for the Ml muscarinic receptor with lower affinity for the M3 and M4 muscarinic receptors (Birdsall & Hulme, 1983;Giachetti et al, 1986;Hammer et al, 1986).…”

“…4-DAMP has a relatively high affinity for M3 muscarinic receptors but also has affinity at Ml and M4 muscarinic receptor subtypes (Dodds et al, 1987;Eltze & Figala, 1988;Eltze et al, 1993;Grimm et al, 1994). HHSiD and p-F-HHSiD have a relatively higher affinity for M3 muscarinic receptors than M2 muscarinic receptors but do have affinity for Ml and M4 muscarinic receptors (Lambrecht et al, 1989;Waelbroeck et al, 1990). Himbacine has relatively high affinity for M2 and M4 muscarinic receptors with lower affinity for Ml and M3 muscarinic receptors (Eglen et al, 1988;Caulfield & Brown, 1991;Miller et al, 1992;Russo et al, 1993).…”