AFFINITY PROFILES OF PIZOTIFEN, KETOTIFEN AND OTHER TRICYCLIC ANTIMUSCARINICS AT MUSCARINIC RECEPTOR SUBTYPE-M1, SUBTYPE-M2 AND SUBTYPE-M3

The affinity of pizotifen, ketotifen and other tricyclic antimuscarinic drugs tor 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.