title: Synthesis, biological evaluation, and docking studies of tetrahydrofuran- cyclopentanone- and cyclopentanol-based ligands acting at adrenergic α₁- and serotonine 5-HT1A receptors.
abstract: A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT(1A) receptors and α(1)-adrenoceptor subtypes was measured by binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone, or cyclopentanol moiety leads to an overall reduction of in vitro affinity at the α(1)-adrenoceptor while both potency and efficacy were increased at the 5-HT(1A) receptor. A significant improvement of 5-HT(1A)/α(1) selectivity was observed in some of the cyclopentanol derivatives synthesized (4acis, 4ccis and trans). Compounds 2a and 4ccis emerged as novel and interesting 5-HT(1A) receptor antagonist (pK(i) = 8.70) and a 5-HT(1A) receptor partial agonist (pK(i) = 9.25, pD(2) = 9.03, E(max) = 47%, 5-HT(1A)/α(1a) = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT(1A) agonism/antagonism activity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche,  Università degli Studi di Modena e Reggio Emilia , Via Campi 183, 41125 Modena, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Prandi
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchini
authors.forename: Leda Ivanova
authors.initials: LI
authors.lastname: Manasieva
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Cilia
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pirona
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054333:Drug Partial Agonism; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C570902:((5,5-diphenyloxolan-2-yl)methyl)(2-phenoxyethyl)amine; C570903:5-((4-(2-methoxyphenyl)piperazin-1-yl)methyl)-2,2-diphenylcyclopentan-1-ol; D003517:Cyclopentanes; D005663:Furans; D008024:Ligands; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A