Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists

J Med Chem. 2006 Feb 9;49(3):1125-39. doi: 10.1021/jm0509501.

Abstract

A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Bradycardia / prevention & control
  • Brain / drug effects
  • Brain / metabolism
  • Dogs
  • Esophagus / drug effects
  • Esophagus / physiology
  • Esters / chemical synthesis
  • Esters / chemistry
  • Esters / pharmacology
  • Female
  • Gastric Emptying / drug effects
  • Guinea Pigs
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Male
  • Mice
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Pyloric Antrum / drug effects
  • Pyloric Antrum / physiology
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Pyrrolizidine Alkaloids / chemical synthesis*
  • Pyrrolizidine Alkaloids / chemistry
  • Pyrrolizidine Alkaloids / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Serotonin 5-HT4 Receptor Agonists*
  • Serotonin 5-HT4 Receptor Antagonists*
  • Structure-Activity Relationship

Substances

  • Amides
  • Benzamides
  • Esters
  • Imidazoles
  • Indoles
  • Pyrroles
  • Pyrrolizidine Alkaloids
  • Serotonin 5-HT4 Receptor Agonists
  • Serotonin 5-HT4 Receptor Antagonists
  • hexahydro-1H-pyrrolizin-1-ylmethyl 1-methyl-1H-indole-3-carboxylate
  • SC 53116
  • SC 53606