Guanylpirenzepine distinguishes between neuronal ml and m4 muscarinic receptor subtypes.

Guanylpirenzepine, a polar, non-quaternary analog of pirenzepine, exhibited a novel binding behavior in rat brain regions: in competition binding experiments against [3H]pirenzepine labeling the M1 receptor in membranes from cerebral cortex, hippocampus and striatum, the compound, differently from pirenzepine, displayed heterogeneous binding curves. Computer assisted analysis of these curves, evidenced the existence of two populations of binding sites: a large proportion (84-89%) of high affinity receptors (KH = 64-92 nM) and a remainder with very low affinity (KL = 19-28 microM). Like pirenzepine, guanylpirenzepine showed low affinity for the glandular M3 and the cardiac M2 receptors when [3H]N-methylscopolamine was used to label the receptors in membranes from these two tissues; affinity values for guanylpirenzepine were 1336 and 5790 nM respectively, vs 323 and 683 nM for pirenzepine.

Affinity profile of the novel muscarinic antagonist, guanylpirenzepine.

The study reports the functional affinity of an amidino derivative of pirenzepine, guanylpirenzepine, for muscarinic receptors mediating relaxation of rat duodenum, inhibition of rabbit vas deferens twitch contraction (both receptors previously classified as M1), guinea pig negative inotropism (M2) and ileal contraction (M3). Unlike pirenzepine, guanylpirenzepine discriminated between duodenum and vas deferens receptors, with a 30-fold greater affinity for the former subtype. The unique selectivity pattern of guanylpirenzepine (duodenum greater than vas deferens greater than ileum greater than atrium) renders it a promising tool for the classification of muscarinic receptor subtypes.

N-(fluoroethyl)(imidazolylphenyl)formamidines. The issue of the active species of mifentidine.

Three N-fluoroethyl-substituted (imidazolylphenyl)formamidine derivatives, namely, 2-fluoroethyl (3b), 2,2-difluoroethyl (3c), and 2,2,2-trifluoroethyl (3d), were prepared to test the effect of fluorine substitution on basicity and, then, on H2-antagonist affinity in comparison with the unsubstituted N-ethyl derivative (3a), taken as a model of mifentidine. Imidazolylphenyl isothiocyanate (1), obtained by reaction of 4-(aminophenyl)imidazole with carbon disulfide and ethyl chloroformate, was condensed with the requisite 2-fluoro-substituted ethylamines to give the intermediate thioureas (2b-d). Desulfurization of these thioureas by Raney nickel furnished the desired formamidines (3b-d).

Pharmacological profile of mifentidine: a novel H2-receptor antagonist.

Mifentidine, a representative compound of a novel class of H2-antagonists, has been investigated for its ability to interact with H2-receptors and to inhibit gastric acid secretion. Affinity estimates (KB) of mifentidine obtained from in vitro studies on cardiac and gastric mucosal histamine (H2) receptors were in the 20-50 nM range. Mifentidine appeared to be endowed with strong anti-secretory properties against histamine-stimulated secretion in the anaesthetized rat and in the conscious dog.

Conformational studies of two histamine H2-receptor antagonistic phenylformamidines: mifentidine and its guanidinothiazole analogue DA 4643.

Two histamine H2-receptor antagonists of the phenylformamidine type, mifentidine (N-isopropyl-N'-(4-1H-imidazol-4-yl-phenyl) formamidine dihydrochloride; I) and DA 4643 (N-methyl-N'-(3-(2-guanidinothiazol-4-yl)-phenyl) formamidine dihydrochloride; II), have been investigated by experimental physico-chemical studies and theoretical conformational analysis. PKa determinations on the two molecules I and II show that these substances exist at physiological pH (7.4) predominantly as their monoprotonated forms at the formamidine moiety.

Cimetidine, ranitidine and mifentidine in specific gastric and duodenal ulcer models.

The protective effect of cimetidine, ranitidine and a newer H2-receptor antagonist, mifentidine (proposed INN), on models of gastric and duodenal damage, caused by activation of H2 receptors, was studied. Gastric erosions were induced in rats by intravenous dimaprit (100 mg/kg) while duodenal damage was investigated in guinea pigs following subcutaneous administration of dimaprit (2 mg/kg, 6 doses). All the compounds reduced or abolished gastric and duodenal damage in rats and guinea pigs, mifentidine being more potent than both cimetidine and ranitidine.

(Imidazolylphenyl)formamidines. A structurally novel class of potent histamine H2 receptor antagonists.

Structure-activity considerations of N alpha-guanylhistamine, the first compound found with detectable H2-antagonist activity, led to the synthesis of a series of conformationally rigid guanylhistamine analogues, namely, (imidazolylphenyl)guanidines, imidazolylbenzamidines, and (imidazolylphenyl)formamidines. It was found that in the guanidine and benzamidine classes, the meta-substituted derivatives (3, 4, 7, and 8) possessed H2-antagonist activity, whereas in the class of formamidines, only the para-substituted derivative 10 was found active. A subsequent increase in the size of the substituent at the formamidino group of 10 led to compounds (15-20) of high H2-antagonist affinity, which was related to the gastric antisecretory effect.

Synthesis and analgesic activity of N-substituted 6,7-benzomorphans.

Some new N-substituted 6,7-benzomorphans were prepared and tested for analgetic activity. The compounds (I) and (II), which proved the most active in a preliminary screening, were submitted to a more detailed investigation, and their ED50 was determined in mice by the phenylquinone, hot-plate and tail-pinch tests. Studies of acute toxicity and physical dependence capacity were also performed.