In vitro characterization of AR-A000002, a novel 5-hydroxytryptamine1B autoreceptor antagonist

The in vitro pharmacological properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel 5-hydroxytryptamine (5-HT)(1B) receptor antagonist, were studied. AR-A000002 bound with high affinity to guinea pig cortex and recombinant guinea pig 5-HT1B receptors (K-i=0.24 and 0.47 nM) and with 10-fold lower affinity to 5-HT1D receptors. The compound displayed weak or no affinity for 63 other binding sites tested. In [S-35]GTPgammaS assays AR-A000002 showed 50% efficacy and inhibited 5-HT stimulation with 66% and a pA(2) value of 8.9. In slices of guinea pig cortex, AR-A000002 enhanced the Outflow Of [H-3]5-HT upon electrical stimulation. The compound blocked sumatriptan-evoked contraction of rabbit saphenous veins without inducing any contraction itself Thus, in these two systems AR-A000002 behaved as a 5-HT1B receptor antagonist. It is concluded that AR-A000002 is a selective high affinity 5HT(1B) receptor ligand that shows partial agonist activity in recombinant systems. In native tissues AR-A000002 behaves as a 5-HT1B receptor antagonist. (C) 2004 Elsevier B.V. All rights reserved.