MDL 72832: a potent and stereoselective ligand at central and peripheral 5-HT1A receptors

Eur J Pharmacol. 1988 Apr 27;149(1-2):107-20. doi: 10.1016/0014-2999(88)90048-9.

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 (pIC50 9.1), selective and stereospecific ligand for central 5-HT1A 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 72832 as a potent, stereoselective ligand with mixed agonist and antagonist properties at central and peripheral 5-HT1A receptors. The similar stereoselective requirements for the recognition site and functional effects provides compelling evidence that the 5-HT1A recognition site is indeed a functional receptor.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Discrimination Learning / drug effects
  • Discrimination, Psychological / drug effects
  • Generalization, Stimulus / drug effects
  • Guinea Pigs
  • Ileum / metabolism
  • In Vitro Techniques
  • Male
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / metabolism*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Neurotransmitter / drug effects
  • Receptors, Serotonin / metabolism*
  • Spiro Compounds / pharmacology*
  • Stereoisomerism

Substances

  • Receptors, Neurotransmitter
  • Receptors, Serotonin
  • Spiro Compounds
  • MDL 72832