New Antipsychotic Agents with Serotonin and Dopamine Antagonist Properties Based on a Pyrrolo[2,1-b][1,3]benzothiazepine Structure

Abstract

The development of a synthetic approach to the novel pyrrolo[2, 1-b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (+/-)-3b was resolved into its enantiomers by using HPLC techniques. In vitro testing confirmed that (-)-3b is a more potent D2 receptor ligand, maintaining high affinity for 5-HT2 receptors. In contrast, the (+)-3b enantiomer presents a 35 times higher affinity for 5-HT2 than for dopamine D2 receptors with a similar dopamine D1 receptor affinity to that of (-)-3b. Overall, (+)-3b shows an "atypical" neuroleptic binding profile, while (-)-3b has a more "classical" profile. Furthermore pharmacological and biochemical testing displayed that the novel benzothiazepine (+/-)-3b is able to increase the extracellular levels of dopamine in the rat striatum and causes a dose-related suppression of apomorphine-induced locomotor activity. At low doses (+/-)-3b does not induce catalepsy, showing atypical antipsychotic properties similar to those of olanzapine. These heterocyclic compouds represent new leads for the development of novel antipsychotic drugs with atypical properties.

Inhibition of Dengue Virus Replication by a Class of Small-Molecule Compounds That Antagonize Dopamine Receptor D4 and Downstream Mitogen-Activated Protein Kinase Signaling

“…Small-molecule compounds with scaffolds and structures similar to those of DHBTs have been researched extensively for their effects on activation and signaling through serotonin and dopamine receptors (24)(25)(26)(27)(28). To investigate the possibility that SKI-417616 is acting through antagonism of serotonin or dopamine receptors, we first consulted a microarray data set to determine the identities of any serotonin or dopamine receptors expressed in HEK293 cells.…”

Five‐Membered Heterocycles: Pyrrole and Related Systems

“…Reaction of 1-alkylpyrroles with 1-(methylthio) morpholine in the presence of acid, or, even better, excess pyridine, gives access to 2,3,4,5-tetra(methylthio)pyrroles [272]. Exposure of 2-thiocyanatopyrrole (see below) to phenyl- [273] or alkylmagnesium bromides [274] provides useful routes to 2-(phenylthio)pyrrole or the corresponding 2-(alkylthio)pyrroles, respectively. Notably, the alkylthio unit serves as a protecting group for the a-position of pyrrole in a new approach to dipyrromethanes [274].…”

Synthetic studies related to the akuammiline alkaloids

“…30 Reaction of the amine with 2,5-dimethoxytetrahydrofuran gave the pyrrole ketone 9a, borohydride reduction of which gave the alcohol 9b. Alcohol 9b was also prepared from 3-hydroxy-3-phenylpropanamine 31 by reaction 32 with 2,5-dimethoxytetrahydrofuran. Attempts to effect ring closure by conversion of the benzylic alcohol in 9b into a triflate were disappointing.…”