98673-90-6Relevant articles and documents
Cholinergic activity of acetylenic imidazoles and related compounds
Moon,Chidester,Heier,Morris,Collins,Russell,Francis,Sage,Sethy
, p. 2314 - 2327 (2007/10/02)
A series of acetylenic imidazoles related to oxotremorine (1a) were prepared and evaluated as cholinergic agents with in vitro binding assays and in vivo pharmacological tests in mice. 1-[4-(1H-Imidazol-1-yl)-2-butynyl]-2-pyrrolidinone (1b) was a cholinergic agonist with one-half the potency of oxotremorine. Analogues of 1b with a 5- or 2-methyl substituent in the imidazole ring (compounds 1c and 1g) were cholinergic partial agonists. Analogues of 1b with a methyl substituent at the 5-position in the pyrrolidinone ring (7b) or at the α-position in the acetylenic chain (8b) were antagonists. Various analogues of these imidazole acetylenes where the pyrrolidinone ring was replaced by an amide, carbamate, or urea residue were prepared. Several compounds which contained 5-methylimidazole as the amine substituent were partial agonists. The activities of the imidazole compounds are compared with those of the related pyrrolidine and dimethylamine analogues. Agonist and antagonist conformations for these compounds at muscarinic receptors are proposed.
Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogues. N-[4-(Tertiary amino)-2-butynyl]-5-methyl-2-pyrrolidones
Amstutz,Ringdahl,Karlen,Roch,Jenden
, p. 1760 - 1765 (2007/10/02)
The enantiomers of three 5-methyl-2-pyrrolidone analogues of the muscarinic agent oxotremorine were synthesized. The pyrrolidine derivative (R)-13 was an antagonist to carbachol in the guinea pig ileum and also showed central and peripheral antimuscarinic activity in vivo. It was more potent and more selective than atropine in antagonizing the central effects of 1. The dimethylamino analogue (R)-14 and the trimethylammonium salt (R)-15 were potent agonists in the guinea pig ileum. (R)-14 showed both central muscarinic (hypothermia) and central antimuscarinic activity (antagonism of oxotremorine-induced tremor) in vivo. The R enantiomers of 13-15 were considerably more potent than the S enantiomers in vivo and in vitro irrespective of whether agonist or antagonist activity was measured. From a comparison of the contribution of the methyl group at the chiral center to the overall affinities it is suggested that agonists and antagonists in this series bind in an essentially identical manner to the muscarinic receptor.
