Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 6, Pages 1926-1938Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.02.015
Keywords
Pain; Calcium channels; T-type calcium channel blockers; Whole patch clamp technique; Dihydropyrimidines; 1,4-Dihydropyridines
Funding
- Egyptian Ministry of Higher Education and Scientific Research
- Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University
- Foundation Grant from the Canadian Institutes of Health Research
- holds a Canada Research Chair
Ask authors/readers for more resources
Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinson's disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the Ca(v)3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of Ca(v)3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated Ca(v)3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in Ca(v)3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40-fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Ca(v)3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity. (C) 2017 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available