Increased gut cholinergic activity and antagonism of 5‐hydroxytryptamine M‐receptors by BRL 24924: potential clinical importance of BRL 24924

1 The mechanisms by which BRL 24924 ([(±)‐(endo)]‐4‐amino‐5‐chloro‐2‐methoxy‐N‐(1‐azabicyclo‐[3.3.1]‐non‐4‐yl) benzamide hydrochloride stimulates gut motility and the relationships between BRL 24924 and 5‐hydroxytryptamine (5‐HT) receptors have been studied. 2 In guinea‐pig isolated ileum, BRL 24924 (10 −4‐ 10 −6 m ) increased electrically‐evoked, cholinergically‐mediated contractions, probably by increasing acetylcholine (ACh) release. This action of BRL 24924 was prevented by the presence of high concentrations of 5‐HT, but not by hexamethonium, phentolamine and propranolol, methysergide or ICS 205–930. 3 The mechanism by which BRL 24924 can increase gut ACh release is not certain, but most likely involves activation of an enteric 5‐HT receptor which differs from those 5‐HT M‐receptors antagonized by ICS 205–930 or by higher concentrations of BRL 24924 in other test systems. 4 BRL 24924 antagonized 5‐HT‐evoked, cholinergically‐mediated contractions of guinea‐pig isolated ileum (pA 2 = 7.56 ± 0.12). Similar and higher concentrations of BRL 24924 did not antagonize contractions evoked by nicotinic receptor stimulation. In rabbit isolated heart, BRL 24924 1–10 n m reduced the tachycardia evoked by 5‐HT. 5 In anaesthetized rats, BRL 24924 0.3–83 nmol kg −1 i.v. antagonized the Bezold‐Jarisch reflex evoked by 5‐HT; the ID 50 for BRL 24924 was 10.2 ± 3.0 nmol kg −1 (3.7 ± 1.1 μg kg −1 ). A direct action of BRL 24924 on nerve function was excluded. 6 In rat cortex, BRL 24924 10 −6 m did not displace [ 3 H]‐5‐HT or [ 3 H]‐ketanserin binding to 5‐HT 1 and 5‐HT 2 receptors. 7 The actions of BRL 24924 are discussed in terms of its potential clinical use as a stimulant of gastric motility and as a 5‐HT M‐receptor antagonist.