Cholinergic activity of acetylenic imidazoles and related compounds

Abstract

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 alpha-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.

New Synthesis of Propargylic Amines from 2-(Bromomethyl)aziridines. Intermediacy of 3-Bromoazetidinium Salts

“…Since many functionalized propargylamines are known to possess various physiological activities, − derivatization of N , N -di(arylmethyl)- N -(2-propynyl)amines 16 was further investigated. To serve this purpose, the Yamaguchi−Hirao alkylation of lithio-acetylides by epoxides with 1.05 equiv of n -BuLi (2.5M in hexane) in the presence of 1.3 equiv of a BF 3 ·THF complex was evaluated .…”

“…IR (NaCl, cm -1 ): νmax 3085, 3062, 3028, 2929, 2804, 1494, 1453, 748, 699. MS (70 eV): m/z (%) 395/7/9 (M + , 7), 316/8 (9), 302/4 (8), 212 (18), 211 (54), 210 (100), 181 (25), 146 (12), 127 (11), 125 (25), 120 (12), 92 (23), 91 (58), 89 (14), 84 (11), 65 (20), 51 (13), 49 (11) 3. Synthesis of 1-Benzyl-3-chloroazetidine 12, Subsequent Quaternization, and Ring Opening.…”

“…Propargylamines are very much in demand in medicinal chemistry, due to the pronounced physiological activities of these compounds and their derivatives. − A very generally occurring mode of action of propargylamines concerns the inhibition of the enzyme monoamine oxidase (MAO, EC 1.4.3.4), − , which makes them potential drugs for treatment of neurotic, psychiatric, and other disorders, such as depression, panic disorder, social phobia, ,, Parkinson's disease, , and Alzheimer's disease. , The biochemical role of the enzyme MAO concerns the oxidation of many monoamines, including important neurotransmitter amines . Other biological activities of propargylamines are for example related to treatment of diabetics, blood lipid lowering activity, and use as fibrin-stabilizing factor inhibitors .…”

Protective efficacy of a hypothermic pharmacological agent in gerbil forebrain ischemia.

“…By 60 minutes, the body temperature had recovered to the predosing level. However, the temperature of the U-80816E-treated gerbils was significantly lower than that of the salinetreated group at 15 hypothermia nearly identical to the first (-1.8°C), demonstrating the consistency of the hypothermic effects of this compound. The baseline temperature before this dose was higher than the initial temperature before the first dose due to the lack of anesthesia at the time of the second dose.…”

Consecutive Multicomponent Reactions: Synthesis of 3-Acyl-4-alkynyl-Substituted 1,3-Thiazolidines

“…2 Oxotremorine and its derivatives, for example, are highly active cholinergic agonists in the treatment of Alzheimer's disease. 3 Propargylamides are also known as useful precursors in the synthesis of dymericin derivatives 1,4 and of heterocyclic compounds by metal-catalyzed cyclization reactions, 5 whereas alkynylamides are used in domino-sequence reactions to produce fluorescent spirocycles. 6 Propargylamides are traditionally prepared by the Ritter reaction, which comprises the reaction of olefins with nitriles.…”