title: Substitution mode of the amide fragment in some new N-[omega-[4-(2-methoxyphenyl)piperazin-1-yl]alkyl]pyrid-2(1H)-ones and their 5-HT1A/5-HT2A activity.
abstract: A series of omega-[4-(2-methoxyphenyl)piperazin-1-yl]alkyl derivatives with terminal pyrid-2(1H)-one fragments was synthesized and evaluated for their 5-HTIA and 5-HT2A activity. Enlargement of the aromatic amide system by its substitution with phenyl and/or p-methoxyphenyl in positions 4, 5 and/or 6, as well as modification of an aliphatic spacer allowed us to better understand structure-activity relationships in that group of compounds. The results of in vitro and in vivo experiments showed that only unsubstituted (1b) and monosubstituted (2b-4b) derivatives with the tetramethylene spacer demonstrated high 5-HTIA receptor affinity (Ki = 15-40 nM) and 5-HT1A/5-HT2A selectivity; they exhibited features of 5-HTIA antagonists. Those results suggested that the mode of substitution of the terminal amide moiety in the tested tetramethylene arylpiperazines was not significant for their 5-HTIA receptor activity. Conformational analysis calculations indicated that despite its great capacity for adaptation at 5-HTIA receptor site, an aryl substituent in position 4 in the pyrid-2(1H)-one ring destabilized the ligand-5-HT1A receptor complex formation in the case of trimethylene derivatives. Diarylsubstituted derivatives (5a-8a and 5b-8b) were characterized by a low 5-HT2A affinity (Ki > 446 nM) regardless of the spacer length, while those with the tetramethylene aliphatic chain had a higher 5-HT2A affinity than the remaining investigated compounds.
authors: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
authors: M H
authors: MH
authors: Paluchowska
authors: R
authors: R
authors: Bugno
authors: S
authors: S
authors: Charakchieva-Minol
authors: A J
authors: AJ
authors: Bojarski
authors: A
authors: A
authors: Wesołowska
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D002855:Chromatography, Thin Layer; D006624:Hippocampus / Q000378:metabolism; D008024:Ligands; D008046:Lip / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012110:Reserpine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018759:Adrenergic Uptake Inhibitors; D008024:Ligands; D011728:Pyridones; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D012110:Reserpine