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

Abstract 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-HT 1B receptors ( K i =0.24 and 0.47 nM) and with 10-fold lower affinity to 5-HT 1D receptors. The compound displayed weak or no affinity for 63 other binding sites tested. In [ 35 S]GTPγS assays AR-A000002 showed 50% efficacy and inhibited 5-HT stimulation with 66% and a p A 2 value of 8.9. In slices of guinea pig cortex, AR-A000002 enhanced the outflow of [ 3 H]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-HT 1B 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-HT 1B receptor antagonist.