Subject(s)
Estradiol Congeners/chemical synthesis , Indoles/chemical synthesis , Animals , Bone Density/drug effects , Cell Line , Estradiol Congeners/chemistry , Estradiol Congeners/metabolism , Estradiol Congeners/pharmacology , Female , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Models, Molecular , Organ Size , Ovariectomy , Radioligand Assay , Rats , Structure-Activity Relationship , Transfection , Uterus/drug effectsABSTRACT
Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Antidepressive Agents/chemical synthesis , Piperazines/chemical synthesis , Receptors, Serotonin/drug effects , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Male , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/classification , Spectrum Analysis , Structure-Activity RelationshipABSTRACT
1'-Substituted spiro[fluorene-9,3'-pyrrolidine-2',5'-diones], 1',1''' - (1,4-piperazinediyldimethylene) bis[spiro[fluorene-9,3'-pyrrolidine-2',5'-dione]], and 1'-arylspiro[fluorene-9,3'-pyrrolidines] were synthesized from spiro[fluorene-9,3'-tetrahydrofuran-2',5'-dione]. The rat passive cutaneous anaphylaxis assay showed that one compound possessed slight antiallergic activity. Synthesis of 3-substituted 1-aryl-4-oxospiro[azetidine-2,9'-fluorenes] and 1,1''-p-phenylenebis[4-oxospiro[azetidine-2,9'-fluorenes]] was achieved via the reaction of appropriate N-fluorenylideneanilines with tert-butylcyanoketene and cyclopentamethyleneketene, respectively.
