Antihistaminic properties of AF-14, an experimental quinuclidine derivative: Discrimination between two histaminergic sites in both guinea-pig ileum and bladder

AF-14 (1-aza-4-phenyltricyclo[6.2.2.0^2,7]dodecan-5-one), a selective antimuscarinic agent, was shown to block the histamine-induced contractile response in Krebs solution in guinea-pig ileum and bladder. Careful linear regression analyses of the concentration-response relationship revealed that AF-14 antagonism consisted of two sequential and distinct phases, corresponding to an early phase and a late phase of the contractile response to histamine. In the late phase, the action of AF-14 was consistent with competitive antagonism, its pA₂ (95% confidence limits) being 5.80-6.06 (ileum) and 5.66-5.80 (bladder). In the early phase, AF-14 almost completely blocked the contractile response at a concentration of 100-300 nM, which was much less than required to block the late phase or cholinergic contractions of the ileum or bladder. It is concluded that AF-14 discriminates between two histamine-sensitive sites that mediate muscle contraction in each of the two organs.