ABSTRACT
A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.
Subject(s)
Adrenergic alpha-Agonists/chemical synthesis , Analgesics/chemical synthesis , Imidazoles/chemical synthesis , Receptors, Adrenergic, alpha-2/drug effects , Thiophenes/chemical synthesis , Adrenergic alpha-Agonists/chemistry , Adrenergic alpha-Agonists/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Brain/metabolism , Electrocardiography , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Male , Mice , Models, Molecular , Rats , Rats, Long-Evans , Rats, Wistar , Receptors, Adrenergic, alpha-2/metabolism , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Analgesics/pharmacology , Oxazoles/pharmacology , Thiazoles/pharmacology , Adrenergic alpha-2 Receptor Antagonists , Adrenergic alpha-Agonists/chemistry , Adrenergic alpha-Agonists/metabolism , Analgesics/chemistry , Analgesics/metabolism , Animals , Dogs , Magnetic Resonance Spectroscopy , Male , Mice , Molecular Structure , Oxazoles/chemistry , Rats , Rats, Wistar , Receptors, Adrenergic, alpha-2/metabolism , Thiazoles/chemistryABSTRACT
4-(Diphenylmethyl)-1-piperidinemethanimine (1) is a potent oral gastric antisecretory agent in rats but contains a strong anticholinergic component. Since a nonanticholinergic gastric antisecretory drug would be useful in the treatment of peptic ulcer disease, a program was initiated by us to find such an agent based on 1. Compound 1 contains structural elements common to the anticholinergics atropine and homatropine. Studies on the structure-activity relationships of these compounds and their derivatives have revealed certain modifications that diminish or abolish anticholinergic activity. The application of these modifications to the design of analogues of 1 afforded an antisecretory compound, 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (3h, fenoctimine), which exhibited no anticholinergic activity. Fenoctimine is undergoing clinical trial as a gastric antisecretory drug.
Subject(s)
Gastric Acid/metabolism , Piperidines/pharmacology , Animals , Anti-Ulcer Agents , Binding, Competitive , Carbachol/pharmacology , Female , Gastric Emptying/drug effects , Quinuclidinyl Benzilate/metabolism , Rats , Receptors, Muscarinic/metabolism , Structure-Activity RelationshipABSTRACT
A series of N-aryl-N'-(1-methyl-2-pyrrolidinylidene)ureas was prepared and screened for pharmacological activity. Congeners possessing either phenyl or phenyl substituted with 4-nitro, 3-bromo, 3-chloro, 3-fluoro, and 3-methyl groups were found to demonstrate anxiolytic activity. 2,6-Disubstitution of the phenyl ring with methyl, chloro, and bromo imparted potent muscle-relaxant properties which appear to be centrally mediated. A significant separation of the anxiolytic and muscle-relaxant properties from other CNS activities, e.g., anticonvulsant, sedative, and hypnotic, was achieved.
