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Verapamil analogues with restricted molecular flexibility.

S Dei1, M N Romanelli, S Scapecchi

  • 1Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.

Journal of Medicinal Chemistry
|July 1, 1991
PubMed
Summary

Restricting verapamil

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Area of Science:

  • Pharmacology
  • Medicinal Chemistry
  • Structural Biology

Background:

  • Verapamil is a phenylalkylamine derivative widely used as a calcium channel blocker.
  • Understanding the active conformation of verapamil is crucial for designing more potent analogues.

Purpose of the Study:

  • To investigate the role of molecular flexibility in verapamil's calcium channel antagonism.
  • To synthesize and characterize novel verapamil analogues with restricted conformations.

Main Methods:

  • Synthesis of cis- and trans-cyclohexane (5a, 5b) and piperidine (6) analogues of verapamil.
  • Conformational analysis using Nuclear Magnetic Resonance (NMR) spectroscopy and theoretical calculations.
  • Assessment of slow calcium channel antagonism on guinea pig aorta strips.

Main Results:

  • The synthesized analogues (5a, 5b, 6) exhibited significantly reduced potency (approximately 100-fold less) compared to verapamil.
  • Despite achieving conformations close to the proposed active conformation of verapamil, the analogues showed diminished calcium channel blocking activity.
  • Loss of rotational flexibility around a key bond was observed in the synthesized analogues.

Conclusions:

  • Flexibility around the bond between the quaternary atom and the adjacent methylene group is essential for verapamil's calcium channel antagonism.
  • Restricting this flexibility, as seen in analogues 5a, 5b, and 6, leads to a substantial loss of potency.
  • Conformational rigidity is a critical factor for maintaining the pharmacological activity of verapamil.

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