MDL 72832: a potent and stereoselective ligand at central and peripheral 5-HT 1A receptors

Abstract

In receptor binding assays (±)MDL 72832, 8-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]8-azaspiro[4,5]decane-7,9-dione, was a potent (pIC 50 9.1), selective and stereospecific ligand for central 5-HT 1A recognition sites. In functional tests, (±)MDL 72832 and its S(−) and R(+) enantiomers blocked stereoselectively the 8-OH-DPAT-induced neuronal inhibition of the transmurally stimulated guinea-pig ileum and the cardiovascular effects of 8-OH-DPAT in anaesthetized rats. In contrast, (±)MDL 72832 and its enantiomers were exclusively ‘8-OH-DPAT-like’ in their ability to fully and stereoselectively generalize to the 8-OH-DPAT discriminative stimulus and, in reserpinised rats, to induce forepaw treading and flat body posture. These results characterize (±)MDL 73832 as a potent, stereoselective ligand with mixed agonist and antagonist properties at central and peripheral 5-HT 1A receptors. The similar stereoselective requirements for the recognition site and functional effects provides compelling evidence that the 5-HT 1A recognition site is indeed a functional receptor.