Ligand based approach to L-type calcium channel by imidazo[2,1-b]thiazole-1,4-dihydropyridines: from heart activity to brain affinity

J Med Chem. 2013 May 23;56(10):3866-77. doi: 10.1021/jm301839q. Epub 2013 May 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channel Blockers / chemical synthesis*
  • Calcium Channel Blockers / pharmacokinetics
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels / drug effects
  • Calcium Channels, L-Type / drug effects*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Computer Simulation
  • Dihydropyridines / chemical synthesis*
  • Dihydropyridines / pharmacology*
  • Guinea Pigs
  • Heart / drug effects*
  • Heart Rate / drug effects
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology*
  • In Vitro Techniques
  • Models, Molecular
  • Muscle, Smooth / drug effects
  • Myocardial Contraction / drug effects
  • Myocardium* / metabolism
  • Myocytes, Cardiac / drug effects
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology*

Substances

  • Calcium Channel Blockers
  • Calcium Channels
  • Calcium Channels, L-Type
  • Dihydropyridines
  • Imidazoles
  • L-type calcium channel alpha(1C)
  • Thiazoles
  • Cacna1d protein, rat