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

1989; Elsevier BV; Volume: 168; Issue: 1 Linguagem: Inglês

10.1016/0014-2999(89)90634-1

1879-0712

Günter Lambrecht, Roland Feifel, Monika Wagner-Röder, Carsten Strohmann, Harald Zilch, Reinhold Tacke, Magalì Waelbroeck, Jean Christophe, Hendrikus Boddeke, E. Mutschler,

Neuropeptides and Animal Physiology

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 M1-(rabbit vas deferens), M2-(guinea-pig atria) and M3-(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 phenyl ring with a methoxy group or a chlorine atom as well as p-fluoro-hexahydro-difenidol displayed the same affinity profile as the parent compound, hexahydro-sila-difenidol: M1 ∼ M3 > M2. A different selectivity pattern was observed for p-fluoro-hexahydro-sila-difenidol: M3 > M1 > M2. This compound exhibited its highest affinity for M3-receptors in guinea-pig ileum (pA2 = 7.84), intermediate affinity for M1-receptors in rabbit vas deferens (pA2 = 6.68) and lowest affinity for the M2-receptors in guinea-pig atria (pA2 = 6.01). This receptor selectivity profile of p-fluoro-hexahydro-sila-difenidol was confirmed in ganglia (M1), atria (M2) and ileum (M3) of the rat. Furthermore, dose ratios obtained with either pirenzepine (M1) or hexahydro-sila-difenidol (M2 and M3) 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.