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J Med Chem. 2015 Aug 13;58(15):5979-88. doi: 10.1021/acs.jmedchem.5b00579. Epub 2015 Jul 23.

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

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†Centre for Brain Research and Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
‡Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, 2 Technology Place, Sydney, NSW 2109, Australia.
§Istituto di Chemica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, I-80078 Pozzuoli, Napoli, Italy.
∥Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185, Rome, Italy.


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.

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