title: 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-HT(1A) 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-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) 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.
authors.affiliation: Laboratoire de Neurobiologie, Université d'Orléans, BP 6759, F-45067 Orléans Cedex 2, France.
authors.forename: M
authors.initials: M
authors.lastname: Picard
authors.forename: S
authors.initials: S
authors.lastname: Morisset
authors.forename: J F
authors.initials: JF
authors.lastname: Cloix
authors.forename: J C
authors.initials: JC
authors.lastname: Bizot
authors.forename: M
authors.initials: M
authors.lastname: Guerin
authors.forename: V
authors.initials: V
authors.lastname: Beneteau
authors.forename: G
authors.initials: G
authors.lastname: Guillaumet
authors.forename: T K
authors.initials: TK
authors.lastname: Hevor
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; C554161:JB-788; D011725:Pyridines; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D058825:Serotonin 5-HT1 Receptor Agonists; D013141:Spiro Compounds; D044282:Receptor, Serotonin, 5-HT1A; D006003:Glycogen; D000242:Cyclic AMP