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

Abstract

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 (pA₂ = 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 nm 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 ID₅₀ 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 [³H]-5-HT or [³H]-ketanserin binding to 5-HT₁ and 5-HT₂ 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.