Novel, highly potent, selective 5-HT2A/D2 receptor antagonists as potential atypical antipsychotics

Taekyu Lee; Albert J Robichaud; Kristopher E Boyle; Yimin Lu; David W Robertson; Keith J Miller; Larry W Fitzgerald; John F McElroy; Brian L Largent

doi:10.1016/s0960-894x(02)01028-4

Novel, highly potent, selective 5-HT2A/D2 receptor antagonists as potential atypical antipsychotics

Bioorg Med Chem Lett. 2003 Feb 24;13(4):767-70. doi: 10.1016/s0960-894x(02)01028-4.

Authors

Taekyu Lee¹, Albert J Robichaud, Kristopher E Boyle, Yimin Lu, David W Robertson, Keith J Miller, Larry W Fitzgerald, John F McElroy, Brian L Largent

Affiliation

¹ Discovery Chemistry, Bristol-Myers Squibb Company, Wilmington, DE 19880, USA. [email protected]

PMID: 12639577
DOI: 10.1016/s0960-894x(02)01028-4

Abstract

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.

MeSH terms

Animals
Antipsychotic Agents / chemical synthesis*
Antipsychotic Agents / pharmacology
Dopamine D2 Receptor Antagonists*
Drug Evaluation, Preclinical
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / pharmacology
Humans
Protein Binding
Radioligand Assay
Rats
Receptor, Serotonin, 5-HT2A / chemistry*
Receptor, Serotonin, 5-HT2C / chemistry*
Seizures / drug therapy
Structure-Activity Relationship

Substances

Antipsychotic Agents
Dopamine D2 Receptor Antagonists
Heterocyclic Compounds, 4 or More Rings
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2C