Synthesis and Structure−Activity Relationship in a Class of Indolebutylpiperazines as Dual 5-HT1A Receptor Agonists and Serotonin Reuptake Inhibitors

• Published in: Journal of medicinal chemistry Vol. 47; no. 19; pp. 4684 - 4692
• Main Authors: Heinrich, Timo, Böttcher, Henning, Gericke, Rolf, Bartoszyk, Gerd D, Anzali, Soheila, Seyfried, Christoph A, Greiner, Hartmut E, van Amsterdam, Christoph
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.09.2004; Amer Chemical Soc
• Subjects: Biological and medical sciences; Chemistry, Medicinal; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Serotoninergic system; ANTIDEPRESSANTS; POTENT; TRANSPORTER; 5-HT(1A); LIGANDS; AFFINITY; PART 1; DOPAMINE-RECEPTORS; BINDING-SITES; DERIVATIVES; Agonist; Nitrile; Rat; Serotonin; Rodentia; Reuptake inhibitor; Vilazodone; In vitro; In vivo; Vertebrata; Mammalia; 5-HT1A Serotonine receptor; Structure activity relation; Animal; Organic fluorine compounds; Benzofuran derivatives; Piperazine derivatives; Indole derivatives; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040793q

Systematic structural modifications of indolealkylphenylpiperazines led to improved selectivity and affinity within this class of 5-HT1A receptor agonists. Introduction of electron-withdrawing groups in position 5 on the indole raises serotonin transporter affinity, and the cyano group proved to be the best substituent here. 5-Fluoro and 5-cyano substituted indoles show comparable results in in vitro and in vivo tests, and bioisosterism between these substituents was supported by calculation of the molecular electrostatic potentials and dipole moments. Compounds showing promising in vitro data were further examined in ex vivo (p-chloroamphetamine assay) and in vivo (ultrasonic vocalization) tests. Optimization of the arylpiperazine moiety indicated that the 5-benzofuranyl-2-carboxamide was best suited to increase 5-HT transporter and 5-HT1A receptor affinity and to suppress D2 receptor binding. 5-{4-[4-(5-Cyano-3-indolyl)butyl]-1-piperazinyl}benzofuran-2-carboxamide 29 (vilazodone, EMD 68843) was identified as a highly selective 5-HT1A receptor agonist [GTPγS, ED50 = 1.1 nM] with subnanomolar 5-HT1A affinity [IC50 = 0.2 nM] and as a subnanomolar 5-HT reuptake inhibitor [RUI = 0.5 nM] showing a great selectivity to other GPCRs (e.g., D2, IC50 = 666 nM).