MDL 72832: a potent and stereoselective ligand at central and peripheral 5-HT1A receptors.
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.
Mir
A K
AK
Merrell Dow Research Institute, Strasbourg, France.
Hibert
M
M
Tricklebank
M D
MD
Middlemiss
D N
DN
Kidd
E J
EJ
Fozard
J R
JR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D005795:Generalization, Stimulus / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D011985:Receptors, Serotonin / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology*; D013237:Stereoisomerism
D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D013141:Spiro Compounds; C056635:MDL 72832