비수기성 항 Histamine제와 대뇌 Muscarine 수용체와의 상호작용

Interaction of Nonsedating Antihistamines with Cerebral Muscarinic Receptors)

Nonsedating antihistamines do not cause sedation in therapeutic doses because these drugs hardly cross the blood-brain barrier. Since most of the peripheral side effects of conventional antihistamines are related to their muscarinic receptor blocking action, the present study was performed to investigate whether nonsedating antihistamines interact with the muscarinic receptors and discriminate the muscarinic receptor subtypes in the rat cerebral microsomal fraction which containes both M1,M2, M3 and M4 receptors. Five nonsedating antihistamines at high concentrations ingibited [3H]QNB binding to the muscarinic receptor in a dose-dependent manner. The inhibition curves of these drugs except loratadine which showed positive cooperativity (nH=1.55) were steep (nH=1), indicating interaction with a single homogenous population of the binding sites. Astemizole, clemizole and mequitazine increased the KD value for [3H]QNB without affecting the binding site concentrations, and this increase in the KD value resulted from the ability of these drugs to slow [3H]QNB-receptor association. The Ki values of astemizole, clemizole and mequitazine for the inhibition of [3H]QNB binding to muscarinic receptor were 0.58, 5.99 and 0.007mcM, respectively. However, loratadine and terfenadine inhibited noncompetitively [3H]QNB binding with the normalized IC50 value of about 2mcM. These results demonstrate that; 1) astemizole, cleizole and mequtazine interact directly with the muscarinic receptor at high concentrations; 2) muscarinic receptor blocking potency of these drugs varies widely among drugs; 3)these drugs do not discriminate between muscarinic receptor subtypes.