title: Synthesis and structure-activity relationship of substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones: potential anxiolytic agents.
abstract: Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.
authors.affiliation: Medicinal Chemistry Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
authors.forename: M
authors.initials: M
authors.lastname: Abou-Gharbia
authors.forename: J A
authors.initials: JA
authors.lastname: Moyer
authors.forename: U
authors.initials: U
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Webb
authors.forename: G
authors.initials: G
authors.lastname: Schiehser
authors.forename: T
authors.initials: T
authors.lastname: Andree
authors.forename: J T
authors.initials: JT
authors.lastname: Haskins
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013843:Thiazines / Q000138:chemical synthesis*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D003499:Cyclic S-Oxides; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D013829:Thiadiazines; D013843:Thiazines; D013844:Thiazoles; D001058:Apomorphine