title: Affinity profiles of pizotifen, ketotifen and other tricyclic antimuscarinics at muscarinic receptor subtypes M1, M2 and M3.
abstract: 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.
authors.affiliation: Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, F.R.G.
authors.forename: M
authors.initials: M
authors.lastname: Eltze
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: G
authors.initials: G
authors.lastname: Lambrecht
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000818:Animals; D003533:Cyproheptadine / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000648:ultrastructure; D007665:Ketotifen / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D018727:Muscarinic Antagonists; D010918:Pizotyline / Q000494:pharmacology*; D011398:Promethazine / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000145:classification / Q000502:physiology; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000648:ultrastructure; D014649:Vas Deferens / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010918:Pizotyline; D003533:Cyproheptadine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D011398:Promethazine; D007665:Ketotifen