Novel, highly potent, selective 5-HT2A/D2 receptor antagonists as potential atypical antipsychotics.
The discovery of N-substituted-pyridoindolines and their binding affinities at the 5-HT(2A), 5-HT(2C) and D(2) receptors, and in vivo efficacy as 5-HT(2A) antagonists is described. The structure-activity relationship of a series of core tetracyclic derivatives with varying butyrophenone sidechains is also discussed. This study has led to the identification of potent, orally bioavailable 5-HT(2A)/D(2) receptor dual antagonists as potential atypical antipsychotics.
Lee
Taekyu
T
Discovery Chemistry, Bristol-Myers Squibb Company, Wilmington, DE 19880, USA. taekyu.lee@bms.com
Robichaud
Albert J
AJ
Boyle
Kristopher E
KE
Lu
Yimin
Y
Robertson
David W
DW
Miller
Keith J
KJ
Fitzgerald
Larry W
LW
McElroy
John F
JF
Largent
Brian L
BL
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004353:Drug Evaluation, Preclinical; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry*; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry*; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D006576:Heterocyclic Compounds, 4 or More Rings; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C