title: 1,3-Dioxolane-based ligands incorporating a lactam or imide moiety: structure-affinity/activity relationship at alpha1-adrenoceptor subtypes and at 5-HT1A receptors.
abstract: A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha(1)-adrenoceptor subtypes and 5-HT(1A) receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective alpha(1a(A))/alpha(1d(D))-adrenoceptor subtype antagonist, over alpha(1b(B)) subtype and 5-HT(1A) receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha(1)/5-HT(1A) selectivity is observed, mainly due to the increase in 5-HT(1A) affinity. In functional experiments lactam derivatives seems to favour 5-HT(1A) receptor antagonism (pKb = 7.20-7.80) and alpha(1B)-adrenoceptor antagonist selectivity (alpha(1B)/alpha(1A) and alpha(1B)/alpha(1D) of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective alpha(1D)-adrenoceptor antagonist (pKb = 8.1 and alpha(1D)/alpha(1A) and alpha(1D)/alpha(1B) selectivity ratios of 16 and 11 respectively) whereas at 5-HT(1A) receptor it is a potent partial agonist (pD2 = 7.98, E(max) = 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT(1A)/agonist and 5HT(1A)/antagonist interaction.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchini
authors.forename: Adolfo
authors.initials: A
authors.lastname: Prandi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Baraldi
authors.forename: Claudia
authors.initials: C
authors.lastname: Sorbi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tait
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Antonio
authors.initials: A
authors.lastname: Cilia
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pirona
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007094:Imides / Q000737:chemistry*; D007769:Lactams / Q000737:chemistry*; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D004148:Dioxolanes; D007094:Imides; D007769:Lactams; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C010962:formal glycol