Graphics computer-aided receptor mapping as a predictive tool for drug design: development of potent, selective, and stereospecific ligands for the 5-HT1A receptor.
A conformational study of four 5-HT1A (serotonin) receptor ligands ((R-(-)-methiothepin, spiperone, (S)-(-)-propranolol, and buspirone) led to the definition of a pharmacophore and a three-dimensional map of the 5-HT1A antagonist recognition site. These models were used to design new compounds and successfully predict their potency, stereospecificity, and selectivity. For example, 8-[4-[(1,4-benzodioxan-2-ylmethyl)amino] butyl]-8-azaspiro[4.5]decane-7,9-dione (1, MDL 72832) has nanomolar affinity (pIC50 = 9.14) for the 5-HT1A binding site in rat frontal cortex. As predicted, the S-(-) enantiomer of 1 was more active than its R-(+) enantiomer (pIC50 = 9.21 and 7.66, respectively) and a naphthalene analogue of 1 displayed the expected improved selectivity.
Hibert
M F
MF
Merrell Dow Research Institute, Strasbourg Center, France.
Gittos
M W
MW
Middlemiss
D N
DN
Mir
A K
AK
Fozard
J R
JR
D000818:Animals; D003196:Computer Graphics; D066298:In Vitro Techniques; D008024:Ligands; D008968:Molecular Conformation; D051381:Rats; D011985:Receptors, Serotonin / Q000032:analysis* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists