Selectivity of Oxomemazine for the M₁ Muscarinic Receptors = 무스카린 M₁ 수용체에 대한 Oxomemazine의 선택성

다국어 초록 (Multilingual Abstract)

The binding characteristics of pirenzepine and oxomemazine to muscarinic receptor were studied to evaluate the selectivity of oxomemazine for the muscarinic receptor subtypes in rat cerebral microsomes. Equilibrium dissociation constant (K_(D)) of (-)-[³H]quinuclidnyl benzilate([³H]QNB) determined from saturation isotherms was 64 pM. Analysis of the pirenzepine inhibition curve of [³H]QNB binding to cerebral microsome indicated the presence of two receptor subtypes with high (K_(i)=16 nM, M₁ receptor) and low (K_(i)=400 nM, M₃receptor) affinity for pirenzepine. Oxomemazine also identified two receptor subtypes with about 20-fold difference in the affinity for high (K_(i)=84nM, O_(H) receptor) and low (K_(i)=1.65 μM, O_(L) receptor) affinity sites. The percentage populations of M₁ and M₃ receptors to the total receptors were 61:39, and those of O_(H) and O_(L) receptors 39:61, respectively. Both pirenzepine wd oxomemazine increased the K_(D) value for [³H]QNB without affecting the binding site concentrations and Hill coefficient for the [³H]QNB binding. Oxomemazine had a 10-fold higher affinity at M₁ receptors than at M₃ receptors, and pirenzepine a 8-fold higher affinity at O_(H) receptors than at O_(L) receptors. Analysis of the shallow competition binding curves of oxomemazine for M₁ receptors and pirenzepine for O_(L) receptors yielded that 69% of M₁ receptors were of O_(H) receptors and remaining 31% of O_(L) receptors, and that 29% of O_(L) receptors were of M₁ receptors and 71% of M₃ receptors. However, M₃ for oxomemazine and O_(H) for pirenzepine were composed of a uniform population. These results suggest that oxomemazine could be classified as a selective drug for M₁ receptors and also demonstrate that rat cerebral microsomes contain three different subtypes of M₁, M₃ and the other site which is different from M₁, M₂ and M₃ receptors.