title: Synthesis and in vivo pharmacology of new derivatives of isothiazolo[5,4-b]pyridine of Mannich base type.
abstract: Recently we reported on 2H-4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridine (V), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3-5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine (2) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V, none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o-OCH3 analog 3a, taken as an example, should be referred back to the conformational restriction incorporated by the o-substitution rather than effects of different lipophlicity or basicity of these compounds.
authors.affiliation: Department of Chemistry of Drugs, Wroclaw University of Medicine, Wroclaw, Poland. malinka@bf.uni.wroc.pl
authors.forename: W
authors.initials: W
authors.lastname: Malinka
authors.forename: Z
authors.initials: Z
authors.lastname: Karczmarzyk
authors.forename: M
authors.initials: M
authors.lastname: Sieklucka-Dziuba
authors.forename: M
authors.initials: M
authors.lastname: Sadowski
authors.forename: Z
authors.initials: Z
authors.lastname: Kleinrok
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D007274:Injections, Intraperitoneal; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018490:Serotonin Agents / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018712:Analgesics, Non-Narcotic; D011725:Pyridines; D018490:Serotonin Agents; D013844:Thiazoles; C476000:isothiazolo(5,4-b)pyridine