title: Distinct Temporal Fingerprint for Cyclic Adenosine Monophosphate (cAMP) Signaling of Indole-2-carboxamides as Allosteric Modulators of the Cannabinoid Receptors.
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.
authors.affiliation: †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.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Cawston
authors.affiliation: ‡Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, 2 Technology Place, Sydney, NSW 2109, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Connor
authors.affiliation: §Istituto di Chemica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, I-80078 Pozzuoli, Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: ∥Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185, Rome, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.affiliation: †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.
authors.forename: Michelle
authors.initials: M
authors.lastname: Glass
mesh_terms: D000494:Allosteric Regulation; D000242:Cyclic AMP / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D015398:Signal Transduction
chemical_list: C572504:5-chloro-3-ethyl-1H-indole-2-carboxylic acid (2-(4-piperidin-1-yl-phenyl)ethyl)amide; D007211:Indoles; D010880:Piperidines; D024661:Potassium Channels, Inwardly Rectifying; D043884:Receptor, Cannabinoid, CB1; D000242:Cyclic AMP