L-4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid

Responses to the nonpeptide angiotensin II agonist 5, 7-Dimethyl-2-ethyl-3-[[2'-([butyloxycarbonyl) aminosulfonyl]-5'-(3-methyoxybenzyl)-[1, 1'-biphenyl]-4-yl]methyl]-3H-imidazo[4,5-b]pyridine (L-163,491) were investigated and compared with responses to angiotensin II, angiotensin IV and norepinephrine in the hindquarters vascular bed of the cat under constant-flow conditions. Injections of L-163,491 into the hindquarter perfusion circuit caused dose-related increases in hindquarters perfusion pressure. In relative terms, angiotensin II was more potent than norepinephrine, which was more potent than angiotensin IV and L-163,491 in increasing hindlimb vascular resistance. The slope of the dose-response curve for L-163,491 was flat, while the apparent affinity of the compound for angiotensin AT(1) receptors was slightly greater than angiotensin IV. Responses to L-163,491 were inhibited by the angiotensin AT(1) receptor antagonist DuP 532 (2-propyl-4-pentafluoroethyl-1-[2'-(1H-tetrazol-5-yl)bipheny l-4-yl)me thyl]imidazole-5-carboxylic acid) and were not altered by the angiotensin AT(2) receptor antagonist PD123,319 (S(+)-1-[[4-(Dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl+ ++) -4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditribluoroacetate). However, the increase in hindlimb perfusion pressure in response to angiotensin II and angiotensin IV was significantly decreased following injection of L-163,491. These data suggest that the nonpeptide angiotensin analog L-163,491 has partial agonist activity, which is dependent on the stimulation of angiotensin AT(1) receptors in the hindquarters vascular bed of the cat.

Complex-formation equilibria between the Ni(II) ion and the natural tripeptide glycyl-L-histidyl-L-lysine have been investigated. Two synthetic analogues, where the histidine residue has been substituted with L-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (L-Spinacine) and L-1,2,3,4-tetrahydro-isoquinolin-3-carboxylic acid (Tic), respectively, have been considered, as well. Different experimental techniques have been employed: potentiometry, calorimetry, visible spectrophotometry and CD spectroscopy. Structural hypotheses on the main complex species are suggested. Evidences on the formation of tetrameric species with the first ligand are shown. No involvement of the side-chain amino group of lysine residue in metal ion coordination was found.