title: Ligand based approach to L-type calcium channel by imidazo[2,1-b]thiazole-1,4-dihydropyridines: from heart activity to brain affinity.
abstract: The synthesis, characterization, and functional in vitro assay in cardiac and smooth muscle (vascular and nonvascular) of a series of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines are reported. To define the calcium blocker nature of the imidazo[2,1-b]thiazole-1,4-DHPs and their selectivity on Cav1.2 and Cav1.3 isoforms, we performed binding studies on guinea pig atrial and ventricular membranes on intact cells expressing the cloned Cav1.2a subunit and on rat brain cortex. To get major insights into the reasons for the affinity for Cav1.2 and/or Cav1.3, molecular modeling studies were also undertaken. Some physicochemical and pharmacokinetic properties of selected compounds were calculated and compared. All the biological data collected and reported herein allowed us to rationalize the structure-activity relationship of the 4-imidazo[2,1-b]thiazole-1,4-DHPs and to identify which of these enhanced the activity at the central level.
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Locatelli
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Matteo
authors.initials: M
authors.lastname: Micucci
authors.forename: Alberto
authors.initials: A
authors.lastname: Leoni
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Bedini
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.forename: Santi Mario
authors.initials: SM
authors.lastname: Spampinato
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003198:Computer Simulation; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008958:Models, Molecular; D009130:Muscle, Smooth / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D007093:Imidazoles; C419385:L-type calcium channel alpha(1C); D013844:Thiazoles; C093712:Cacna1d protein, rat