Arylpiperazine derivatives of 3-propyl-beta-tetralonohydantoin as new 5-HT1A and 5-HT2A receptor ligands.
A series of new analogues of 3-[3-(4-arylpiperazinyl)-propyl]-cyclo-hexane-1',5-spirohydantoin (2), with aromatic ring fused in amide moiety (4-9) were synthesized and evaluated for affinity at 5-HTIA and 5-HT2A receptors. The influence of the substitution mode in the phenyl ring of phenylpiperazine moiety on the affinity for both receptors has been discussed. The most potent 5-HTIA (9, Ki = 53 nM) and 5-HT2A (4, 6, 8 and 9; Ki = 14-76 nM) ligands were evaluated in in vivo tests. The obtained results indicate that all in vivo tested compounds showed pharmacological profile of 5-HT2A antagonists. Additionally, a m-CF3 derivative (9), behaved like a partial agonist (agonist of pre- and antagonist of postsynaptic) of 5-HTIA receptors and may offer a new lead for the development of potential psychotropic agents.
Byrtus
H
H
Department of Pharmaceutical Chemistry, Collegium Medicum, Jagiellonian University, Kraków, Poland.
Pawłowski
M
M
Duszyńska
B
B
Wesołowska
A
A
Chojnacka-Wójcik
E
E
Bojarski
A J
AJ
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D019416:Head Movements / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008046:Lip / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
C459880:7,8-benzo-1,3-diazaspiro-(4,5)-decane-2,4-dione; D006827:Hydantoins; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; D013141:Spiro Compounds