Eltze M, Mutschler E, Lambrecht G
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, F.R.G.
Eur J Pharmacol. 1992 Feb 18;211(3):283-93. doi: 10.1016/0014-2999(92)90383-f.
The affinity of pizotifen, ketotifen and other tricyclic antimuscarinic drugs for different muscarinic receptor subtypes was investigated in vitro in functional experiments with field-stimulated vas deferens of the rabbit (M1 and M2 receptors) and with ileum and trachea of the guinea-pig (M3 receptors). All compounds were competitive antagonists in the three tissues. Like the close analogue cyproheptadine (pA2 = 7.99-8.08), pizotifen (pA2 = 7.23-7.81) and ketotifen (pA2 = 6.34-6.99) were devoid of selectivity for the receptor subtypes studied. Thiazinamium, although exhibiting high affinity for muscarinic receptors (pA2 = 7.83-8.51), was found to be non-selective. In contrast, the novel pirenzepine analogue nuvenzepine was selective for M1 receptors (pA2 = 6.63-7.74). The lack of selectivity of cyproheptadine, pizotifen and ketotifen is reflected in the chemical structures of these drugs. All three antagonists are composed of a very similar tricyclic ring system linked to a 1-methyl-4-piperidylene ring. The finding that thiazinamium, pizotifen and cyproheptadine were potent muscarinic antagonists and possessed non-selective affinity characteristics may have therapeutic implications.
在体外实验中，利用兔的输精管（M1和M2受体）以及豚鼠的回肠和气管（M3受体）进行功能实验，研究了匹莫齐特、酮替芬和其他三环类抗毒蕈碱药物对不同毒蕈碱受体亚型的亲和力。所有化合物在这三种组织中均为竞争性拮抗剂。与结构类似的赛庚啶（pA2 = 7.99 - 8.08）一样，匹莫齐特（pA2 = 7.23 - 7.81）和酮替芬（pA2 = 6.34 - 6.99）对所研究的受体亚型均无选择性。噻嗪铵虽然对毒蕈碱受体表现出高亲和力（pA2 = 7.83 - 8.51），但被发现无选择性。相比之下，新型哌仑西平类似物纽凡西平对M1受体具有选择性（pA2 = 6.63 - 7.74）。赛庚啶、匹莫齐特和酮替芬缺乏选择性反映在这些药物的化学结构上。这三种拮抗剂均由一个非常相似的三环系统与一个1 - 甲基 - 4 - 哌啶环相连组成。噻嗪铵、匹莫齐特和赛庚啶是强效毒蕈碱拮抗剂且具有非选择性亲和力特征这一发现可能具有治疗意义。
