title: 1,3-Dioxolane-based ligands as rigid analogues of naftopidil: structure-affinity/activity relationships at alpha1 and 5-HT1A receptors.
abstract: Conformational restriction of naftopidil proved to be compatible with binding at alpha(1) adrenoceptor subtypes and 5-HT receptor 1A (5-HT(1A)), and led to the discovery of a new class of ligands with a 1,3-dioxolane (1,3-oxathiolane, 1,3-dithiolane) structure. Compound 7 shows the highest affinity toward alpha(1a) and alpha(1d) adrenoceptor subtypes (pK(i) alpha(1a) = 9.58, pK(i) alpha(1d) = 9.09) and selectivity over 5-HT(1A) receptors (alpha(1a)/5-HT(1A) = 100, alpha(1d)/5-HT(1A) = 26). In functional experiments it behaves as a potent competitive alpha(1a) and alpha(1d) adrenoceptor antagonist (pK(b) alpha(1A) = 8.24, pK(b) alpha(1D) = 8.14), whereas at 5-HT(1A) receptors it is a potent partial agonist (pD(2) = 8.30). Compounds 8 and 10 display high affinity (pK(i) = 8.29 and 8.26, respectively) and selectivity for 5-HT(1A) (5-HT(1A)/alpha(1) = 18 and 10). In functional experiments at the 5-HT(1A) receptor, compound 8 appears to be neutral antagonist (pK(b) = 7.29), whereas compound 10 is a partial agonist (pD(2) = 6.27). Therefore, 1,3-dioxolane-based ligands are a versatile class of compounds useful for the development of more selective ligands for one (alpha(1)) or the other (5-HT(1A)) receptor system.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sorbi
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tait
authors.forename: Adolfo
authors.initials: A
authors.lastname: Prandi
authors.forename: Rossella
authors.initials: R
authors.lastname: Gallesi
authors.forename: Piero
authors.initials: P
authors.lastname: Angeli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pirona
authors.forename: Elena
authors.initials: E
authors.lastname: Poggesi
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D004148:Dioxolanes; D008024:Ligands; D009281:Naphthalenes; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C064357:naftopidil; C010962:formal glycol