Structure-intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity.
Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)(1A) ligands. In order to trace structure-intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives with different cyclic imide/amide termini, and their flexible, tetramethylene analogues were synthesized and pharmacologically evaluated for 5-HT(1A) receptors. In vitro binding experiments revealed that all the compounds were potent 5-HT(1A) receptor agents (K(i) = 1.9-74 nM). Some derivatives tested additionally showed also high affinity for alpha(1)-adrenergic receptors (K(i) = 2.9-101 nM) and for 5-HT(7) receptors. Functional in vivo examination revealed that rigid ligands with o-OCH(3) group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT(1A) receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF(3) substituted derivatives as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivatives tested, that is, postsynaptic 5-HT(1A) antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats.
Bojarski
Andrzej J
AJ
Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smetna, Kraków, Poland. bojarski@if-pan.krakow.pl
Paluchowska
Maria H
MH
Duszyńska
Beata
B
Bugno
Ryszard
R
Kłodzińska
Aleksandra
A
Tatarczyńska
Ewa
E
Chojnacka-Wójcik
Ewa
E
D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D000577:Amides / Q000737:chemistry*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004327:Drinking Behavior / Q000187:drug effects; D007094:Imides / Q000737:chemistry*; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000316:Adrenergic alpha-Agonists; D000577:Amides; D014151:Anti-Anxiety Agents; D003510:Cyclohexanes; D007094:Imides; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A