Distinct Temporal Fingerprint for Cyclic Adenosine Monophosphate (cAMP) Signaling of Indole-2-carboxamides as Allosteric Modulators of the Cannabinoid Receptors

Erin E. Cawston, Mark Connor, Vincenzo Di Marzo, Romano Silvestri, Michelle Glass*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

ORG27569 (1) is an allosteric modulator of CB1. 1 produces a distinct cAMP temporal fingerprint with complex time-dependent modulation of agonist-mediated responses. The aim of this study was to characterize the cAMP signaling response of indole-2-carboxamides structurally correlated to 1 for both CB1 and CB2. We show that at CB1 1, 10, 13, and 18 display a delay in inhibiting CP55,940-mediated cAMP inhibition, whereas compounds 7, 14, 15, 16, 20, and 22 act immediately. To further characterize this, compounds 1, 10, 13, 14, 15, 18, and 20 were tested for their influence on CP55,940-mediated hyperpolarization in AtT20-hCB1 cells. Intriguingly, all compounds generated a response similar to that of 1, producing no decrease in CB1-mediated peak hyperpolarization at concentrations up to 10 μM but enhancing the rate at which the channel repolarizes. Additionally, we show that compounds 5, 10, and 20 indole-2-carboxamides modulate cAMP signaling through CB2.

Original languageEnglish
Pages (from-to)5979-5988
Number of pages10
JournalJournal of Medicinal Chemistry
Volume58
Issue number15
DOIs
Publication statusPublished - 23 Jul 2015

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