title: Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry and Department of Pharmacology, Pfizer, 4901 Searle Parkway, Skokie, IL 60077, USA. dbecke3@luc.edu
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Becker
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Flynn
authors.forename: Alan E
authors.initials: AE
authors.lastname: Moormann
authors.forename: Roger
authors.initials: R
authors.lastname: Nosal
authors.forename: Clara I
authors.initials: CI
authors.lastname: Villamil
authors.forename: Richard
authors.initials: R
authors.lastname: Loeffler
authors.forename: Gary W
authors.initials: GW
authors.lastname: Gullikson
authors.forename: Chafiq
authors.initials: C
authors.lastname: Moummi
authors.forename: Dai-C
authors.initials: DC
authors.lastname: Yang
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001919:Bradycardia / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011706:Pyloric Antrum / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001549:Benzamides; D004952:Esters; D007093:Imidazoles; D007211:Indoles; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; C508998:hexahydro-1H-pyrrolizin-1-ylmethyl 1-methyl-1H-indole-3-carboxylate; C074211:SC 53116; C083229:SC 53606