title: Synthesis and evaluation of 1,4-dihydropyridine derivatives with calcium channel blocking activity.
abstract: 1,4-Dihydropyridines (DHPs) are an important class of L-type calcium channel blockers that are used to treat conditions such as hypertension and angina. Their primary target in the cardiovascular system is the Cav1.2 L-type calcium channel isoform, however, a number of DHPs also block low-voltage-activated T-type calcium channels. Here, we describe the synthesis of a series of novel DHP derivatives that have a condensed 1,4-DHP ring system (hexahydroquinoline) and report on their abilities to block both L- and T-type calcium channels. Within this series of compounds, modification of a key ester moiety not only regulates the blocking affinity for both L- and T-type channels, but also allows for the development of DHPs with 30-fold selectivity for T-type channels over the L-type. Our data suggest that a condensed dihydropyridine-based scaffold may serve as a pharmacophore for a new class of T-type selective inhibitors.
authors.affiliation: Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Bladen
authors.forename: Miyase Gözde
authors.initials: MG
authors.lastname: Gündüz
authors.forename: Rahime
authors.initials: R
authors.lastname: Şimşek
authors.forename: Cihat
authors.initials: C
authors.lastname: Şafak
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; C038806:1,4-dihydropyridine