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

Increased gut cholinergic activity and antagonism of 5‐hydroxytryptamine M‐receptors by BRL... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

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

British Journal of Pharmacology, Volume 91 (1) – May 1, 1987

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Publisher
Wiley
Copyright
1987 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1111/j.1476-5381.1987.tb08985.x
Publisher site
See Article on Publisher Site

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.

Journal

British Journal of PharmacologyWiley

Published: May 1, 1987

References

  • Atropine‐resistant longitudinal muscle spasm due to excitation of non‐cholinergic neurones in Auerbach's plexus
    Ambache, Ambache; Freeman, Freeman
  • 5‐Hydroxytryptamine receptor antagonism by metoclopramide and ICS 205‐930 in the guinea‐pig leads to enhancement of contractions of stomach muscle strips induced by electrical field stimulation and facilitation of gastric emptying in vivo
    Buchheit, Buchheit; Costall, Costall; Engel, Engel; Gunning, Gunning; Naylor, Naylor; Richardson, Richardson
  • The sites of action of 5‐hydroxytryptamine in nerve‐muscle preparations from the guinea‐pig small intestine and colon
    Costa, Costa; Furness, Furness
  • Two types of receptor for 5‐hydroxytryptamine on the cholinergic nerves of the guinea‐pig myenteric plexus
    Kilbinger, Kilbinger; Pfeuffer‐Friederich, Pfeuffer‐Friederich
  • Inhibition of cisplatin‐induced vomiting by selective 5‐hydroxytryptamine M‐receptor antagonism
    Miner, Miner; Sanger, Sanger
  • Three different ways in which 5‐ hydroxytryptamine can affect cholinergic activity in guinea‐pig isolated ileum
    Sanger, Sanger
  • Effects of metoclopramide and domperidone on cholinergically‐mediated contractions of human isolated stomach muscle
    Sanger, Sanger

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