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Synthesis and structure-activity relationships of a series of pyrrole cannabinoid receptor agonists

  • Author(s): Tarzia, G
  • Duranti, A
  • Tontini, A
  • Spadoni, G
  • Mor, M
  • Rivara, S
  • Plazzi, PV
  • Kathuria, S
  • Piomelli, D
  • et al.
Abstract

We designed and synthesized a series of pyrrole derivatives with the aim of investigating the structure-activity relationship (SAR) for the binding of non-classical agonists to CB1 and CB2 cannabinoid receptors. Superposition of two pyrrole-containing cannabinoid agonists, JWH-007 and JWH-161, allowed us to identify positions 1, 3 and 4 of the pyrrole nucleus as amenable to additional investigation. We prepared the 1-alkyl-2,5-dimethyl-3,4-substituted pyrroles 10a-e, 11a-d, 17, 21, 25 and the tetrahydroindole 15, and evaluated their ability to bind to and activate cannabinoid receptors. Noteworthy in this set of compounds are the 4-bromopyrrole 11a, which has an affinity for CB1 and CB2 receptors comparable to that of well-characterized heterocyclic cannabimimetics such as Win-55,212-2; the amide 25, which, although possessing a moderate affinity for cannabinoid receptors, demonstrates that the 3-naphthoyl group, commonly present in indole and pyrrole cannabimimetics, can be substituted by alternative moieties; and compounds 10d, 11d, showing CB1 partial agonist properties. © 2003 Elsevier Ltd. All rights reserved.

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