Increased gut cholinergic activity and antagonism of 5-hydroxytryptamine M-receptors by BRL 24924: potential clinical importance of BRL 24924.
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. In guinea-pig isolated ileum, BRL 24924 (10(-14)-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. 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. 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. 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 microgram kg-1). A direct action of BRL 24924 on nerve function was excluded. 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. 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.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011950:Receptors, Cholinergic / Q000502:physiology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011950:Receptors, Cholinergic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C053006:renzapride