Abstract
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
MeSH terms
-
Alkylation
-
Antipsychotic Agents / chemical synthesis*
-
Antipsychotic Agents / pharmacology*
-
Cytochrome P-450 Enzyme System / chemistry
-
Cytochrome P-450 Enzyme System / metabolism
-
Dopamine Antagonists / chemical synthesis
-
Dopamine Antagonists / pharmacology
-
Dopamine D2 Receptor Antagonists
-
Drug Design
-
Humans
-
Receptor, Serotonin, 5-HT2A / drug effects
-
Receptor, Serotonin, 5-HT2C / drug effects
-
Receptors, Dopamine D3 / antagonists & inhibitors
-
Receptors, Serotonin / drug effects
-
Recombinant Proteins / drug effects
-
Serotonin Antagonists / chemical synthesis
-
Serotonin Antagonists / pharmacology
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis
-
Sulfonamides / pharmacology
Substances
-
Antipsychotic Agents
-
Dopamine Antagonists
-
Dopamine D2 Receptor Antagonists
-
Receptor, Serotonin, 5-HT2A
-
Receptor, Serotonin, 5-HT2C
-
Receptors, Dopamine D3
-
Receptors, Serotonin
-
Recombinant Proteins
-
Serotonin Antagonists
-
Sulfonamides
-
serotonin 6 receptor
-
Cytochrome P-450 Enzyme System