5‐ C hloroindole: a potent allosteric modulator of the 5‐ HT 3 receptor

Background and Purpose The 5‐ HT 3 receptor is a ligand‐gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators ( PAMs ) identified to date have low affinity, which hinders investigation because of non‐selective effects at pharmacologically active concentrations. The present study identifies 5‐chloroindole ( C l‐indole) as a potent PAM of the 5‐ HT 3 receptor. Experimental Approach 5‐ HT 3 receptor function was assessed by the increase in intracellular calcium and single‐cell electrophysiological recordings in HEK 293 cells stably expressing the h5‐ HT 3 A receptor and also the mouse native 5‐ HT 3 receptor that increases neuronal contraction of bladder smooth muscle. Key Results Cl‐indole (1–100 μ M ) potentiated agonist (5‐ HT ) and particularly partial agonist [( S )‐zacopride, DDP 733, RR 210, quipazine, dopamine, 2‐methyl‐5‐ HT , SR 57227 A , meta chlorophenyl biguanide] induced h5‐ HT 3 A receptor‐mediated responses. This effect of C l‐indole was also apparent at the mouse native 5‐ HT 3 receptor. Radioligand‐binding studies identified that C l‐indole induced a small (∼twofold) increase in the apparent affinity of 5‐ HT for the h5‐ HT 3 A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. C l‐indole was able to reactivate desensitized 5‐ HT 3 receptors. In contrast to its effect on the 5‐ HT 3 receptor, C l‐indole did not alter human nicotinic α7 receptor responses. Conclusions and Implications The present study identifies C l‐indole as a relatively potent and selective PAM of the 5‐ HT 3 receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5‐ HT 3 receptor and may assist the discovery of novel therapeutic drugs targeting this receptor. Linked Articles Recent reviews on allosteric modulation can be found at: Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476‐5381.2012.02223.x Roche D, Gil D and Giraldo J (2013). Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two‐state and operational models. British Journal of Pharmacology 169: 1189–1202. doi: 10.1111/bph.12231