Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition

Pieter Smid; Hein K A C Coolen; Hiskias G Keizer; Rolf van Hes; Jan-Peter de Moes; Arnold P den Hartog; Bob Stork; Rob H Plekkenpol; Leonarda C Niemann; Cees N J Stroomer; Martin Th M Tulp; Herman H van Stuivenberg; Andrew C McCreary; Mayke B Hesselink; Arnoud H J Herremans; Chris G Kruse

doi:10.1021/jm050148z

Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition

J Med Chem. 2005 Nov 3;48(22):6855-69. doi: 10.1021/jm050148z.

Authors

Pieter Smid¹, Hein K A C Coolen, Hiskias G Keizer, Rolf van Hes, Jan-Peter de Moes, Arnold P den Hartog, Bob Stork, Rob H Plekkenpol, Leonarda C Niemann, Cees N J Stroomer, Martin Th M Tulp, Herman H van Stuivenberg, Andrew C McCreary, Mayke B Hesselink, Arnoud H J Herremans, Chris G Kruse

Affiliation

¹ Solvay Pharmaceuticals Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. pieter.smid@solvay.com

PMID: 16250644
DOI: 10.1021/jm050148z

Abstract

A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Animals
Antipsychotic Agents / chemical synthesis*
Antipsychotic Agents / pharmacokinetics
Antipsychotic Agents / pharmacology
Benzoxazines / chemical synthesis*
Benzoxazines / pharmacokinetics
Benzoxazines / pharmacology
Biological Transport
CHO Cells
Cell Line
Cricetinae
Cricetulus
Dopamine D2 Receptor Antagonists*
Indoles / chemical synthesis*
Indoles / pharmacokinetics
Indoles / pharmacology
Male
Models, Molecular
Piperazines / chemical synthesis*
Piperazines / pharmacokinetics
Piperazines / pharmacology
Rats
Selective Serotonin Reuptake Inhibitors / chemical synthesis*
Selective Serotonin Reuptake Inhibitors / pharmacokinetics
Selective Serotonin Reuptake Inhibitors / pharmacology
Structure-Activity Relationship

Substances

8-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)-4H-benzo(1,4)oxazin-2-methyl-3-one
ATP Binding Cassette Transporter, Subfamily B, Member 1
Antipsychotic Agents
Benzoxazines
Dopamine D2 Receptor Antagonists
Indoles
Piperazines
Serotonin Uptake Inhibitors