71970-74-6Relevant academic research and scientific papers
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.
5-Methyl-2-pyrrolidone Analogues of Oxotremorine as Selective Muscarinic Agonists
Ringdahl, Bjoern
, p. 683 - 688 (2007/10/02)
A series of N-(4-amino-2-butynyl)-5-methyl-2-pyrrolidones modified only in the amino group was synthesized.The compounds were agonists, partial agonists, and antagonists on the isolated guinea pig ileum.They had greater affinity and lower intrinsic efficacy at ileal muscarinic receptors than the identically modified N-(4-amino-2-butynyl)-2-pyrrolidones and N-(4-amino-2-butynyl)succinimides.Dissociation constants in the three series were correlated, suggesting that the compounds had similar mode of binding to muscarinic receptors.The 5-methyl-2-pyrrolidones were 10- to 20-fold less potent as muscarinic agonists on the guinea pig urinary bladder than on the ileum and also elicited lower relative maximal responses on the bladder.For example, the trimethylammonium (9) and azetidino (10) analogues were equipotent (EC60 = 0.2 μM) with the selective muscarinic stimulant N-(1-methyl-4-pyrrolidino-2-butynyl)-N-methylacetamide, BM 5 (2), as agonists on the ileum, but on the bladder 8 and 10 were relatively weak agonists, whereas 2 was an antagonist.Compound 10, like 2 and the dimethylamino analogue 8, also differentiated between centrally mediated muscarinic effects in vivo as it was potent in producing analgesia and hypothermia but did not elicit tremor.Instead, 10 antagonized oxotremorine-induced tremor.Thus, 10 resembled 2 in its actions except that the greater intrinsic efficacy of 10 shifted the balance between agonist and antagonist properties slightly toward agonism.Manipulation of intrinsic efficacy by minor changes in chemical structure is emphasized as a means of attaining selectivity.
