항 Histamine제와 Muscarinic Receptor와의 상호작용(II) -대뇌 Muscarinic M1 Receptor에 대한 작용-

Interaction of Antihistaminics with Muscarinic Receptor(II) -Action on the cerebral muscarinic M1 Receptor-

A single uniform population of specific, saturable, high affinity binding site of [3H] guinuclidinyl benzilate(QNB) was identified in the rat cerebral microsomes. The Kd value(37.2pM) for [3H]QNB calculated from the kinetically derived rate constants was in agreement with the Kd value(48.9pM) determined by analysis of saturation isotherms at various receptor concentrations. Dimenhydrinate(DMH), histamine H1-blocker, increased Kd value for [3H] QNB without affecting the binding site concentrations and this effect resulted from the ability of DMH to Slow [3H]QNB-receptor association. Pirenzepine inhibition curve of [3H]QNB binding was shallow(nH = 0.52) indicating the presence of two receptor subtypes with high (M1-site) and low(M2-site) affinity for pirenzepine. Analysis of these inhibition curves yielded that 68% of the total receptor populations were of the M1-subtype and the remaining 32% of the M2subtype. Ki values for the M1- and M2-subtypes were 2.42nM and 629.3nM, respectively. Ki values for H1-blockers that inhibited [3H]QNB binding varied with a wide range (0.02-2.5mcM). The Pseudo-Hill coefficients for inhibition of [3H]QNB binding by most of H1-blockers examined except for oxomemazine inhibition of [3H]QNB binding were close to one. The inhibition curve for oxomemazine in competition with [3H]QNB was shallow(nH = 0.74) indicating the presence of two receptor populations with different affinities for this drug. The proportion of high and low affinity was 33:67. The Ki values for oxomemazine were 0.045 +/- 0.016mcM for high affinity and 1.145+/-0.232mcM for low affinity sites. These data indicate that muscarinic receptor blocking potency of H1-blockers varies widely between different drugs and that most of H1-blockers examined are nonselective antagonist for the muscarinic receptor subtypes, whereas oxomemazine might be capable of distinguishing between subclasses of muscarinic receptor.