Abstract
Spiperone (1) is a widely used pharmacological tool that acts as a potent dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A antagonist. Although spiperone also binds at 5-HT2C receptors, it is one of the very few agents that display some (ca. 1000-fold) binding selectivity for 5-HT2A versus 5-HT2C receptors and, hence, might serve as a useful template for the development of novel 5-HT2A antagonists if the impact of its various substituent groups on binding was known. In the present investigation we focused on the 1, 3,8-triazaspiro[4.5]decanone portion of spiperone and found that replacement of the N1-phenyl group with a methyl group only slightly decreased affinity for cloned rat 5-HT2A receptors. However, N1-methyl derivatives displayed significantly reduced affinity for 5-HT1A, 5-HT2C, and dopamine D2 receptors. Several representative examples were shown to behave as 5-HT2 antagonists. As such, N1-alkyl analogues of spiperone may afford entry into a novel series of 5-HT2A-selective antagonists.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
3T3 Cells
-
Animals
-
Dopamine Antagonists / chemical synthesis*
-
Dopamine Antagonists / chemistry
-
Dopamine Antagonists / metabolism
-
Dopamine Antagonists / pharmacology
-
Dopamine D2 Receptor Antagonists
-
Mice
-
Radioligand Assay
-
Rats
-
Receptor, Serotonin, 5-HT2A
-
Receptor, Serotonin, 5-HT2C
-
Receptors, Dopamine D2 / metabolism
-
Receptors, Serotonin / drug effects*
-
Receptors, Serotonin / metabolism
-
Receptors, Serotonin, 5-HT1
-
Recombinant Proteins / antagonists & inhibitors
-
Recombinant Proteins / metabolism
-
Serotonin Antagonists / chemical synthesis*
-
Serotonin Antagonists / chemistry
-
Serotonin Antagonists / metabolism
-
Serotonin Antagonists / pharmacology
-
Spiperone / analogs & derivatives*
-
Spiperone / chemical synthesis*
-
Spiperone / chemistry
-
Spiperone / pharmacology
-
Structure-Activity Relationship
Substances
-
Dopamine Antagonists
-
Dopamine D2 Receptor Antagonists
-
Receptor, Serotonin, 5-HT2A
-
Receptor, Serotonin, 5-HT2C
-
Receptors, Dopamine D2
-
Receptors, Serotonin
-
Receptors, Serotonin, 5-HT1
-
Recombinant Proteins
-
Serotonin Antagonists
-
Spiperone