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.
Subject(s)
Maze Learning/drug effects , Motor Activity/drug effects , Pyridines/pharmacology , Receptor, Serotonin, 5-HT1A/physiology , Serotonin 5-HT1 Receptor Agonists/pharmacology , Spiro Compounds/pharmacology , Animals , Anti-Anxiety Agents/pharmacology , Antipsychotic Agents/pharmacology , Brain/drug effects , Brain/metabolism , Cell Line , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Dopamine D2 Receptor Antagonists , Glycogen/metabolism , Humans , Male , Mice , Radioligand Assay , Receptors, Dopamine D2/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/antagonists & inhibitorsABSTRACT
Coupling of five amines on the 7-methoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline core was achieved and afforded, in particular, an opened analogue of the natural alkaloid wakayin. Evaluation of cytotoxic activity of compounds 2, 10-13 on L1210 cells afforded IC50 in the range 0.25 5.3 microM.