Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist

Abstract A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT1A receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT1A receptor expressed in human embryonic kidney 293 (HEK-293) cells with a Ki value of 0.8 nM. Its binding affinity is in the same range as that observed for the (±)8-OH-DPAT, a reference 5HT1A agonist compound. Notably, JB-788 only bound weakly to 5-HT1B or 5-HT2A receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, α2 , β1 and β2 adrenergic receptors, or dopaminergic D1 receptors. JB-788 was found to display substantial binding affinity for dopaminergic D2 receptors and, to a lesser extend to α1 adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT1A , thus acting as a potent 5-HT1A receptor agonist (Emax. 75%, EC50 3.5 nM). JB-788 did not exhibit any D2 receptor agonism but progressively inhibited the effects of quinpirole, a D2 receptor agonist, in the cAMP accumulation test with a Ki value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.