Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives Differentially Modulate Affinity for 5-HT1A, D4.2, and α					2A Receptors: Synthesis and In Vitro Radioligand Binding Studies

Amaury Graulich; Marc Léonard; Mélissa Résimont; Xi-Ping Huang; Bryan L. Roth; Jean-François Liégeois

doi:10.1071/CH09353

RESEARCH ARTICLE

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives Differentially Modulate Affinity for 5-HT_1A, D4.2, and α _2A Receptors: Synthesis and In Vitro Radioligand Binding Studies

Amaury Graulich ^A , Marc Léonard ^A , Mélissa Résimont ^A , Xi-Ping Huang ^B , Bryan L. Roth ^B and Jean-François Liégeois ^A ^C

+ Author Affiliations

- Author Affiliations

^A Drug Research Center, Laboratory of Medicinal Chemistry, University of Liège, Avenue de l’Hôpital 1 (B36), B-4000 Liège 1, Belgium.

^B Department of Pharmacology, School of Medicine and Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, CB 7365, Chapel Hill, NC 27599, USA.

^C Corresponding author. Email: JF.Liegeois@ulg.ac.be

Australian Journal of Chemistry 63(1) 56-67 https://doi.org/10.1071/CH09353
Submitted: 20 June 2009 Accepted: 13 August 2009 Published: 8 January 2010

Abstract

A series of substituted 4-aryl-piperazine-ethyl heteroarylcarboxamides were prepared and tested in in vitro radioligand binding studies. The presence of a quinoxaline has a favourable impact in terms of serotonin 5-HT_1A versus dopamine D4.2 receptor selectivity. Compounds with a 3-CF₃ group at the distal phenyl ring are the most effective in terms of affinity and selectivity for 5-HT_1A versus D4.2 receptors. A 4-phenyl-1,2,3,6-tetrahydropyridine in place of the corresponding 4-phenyl-piperazine side chain is also favourable not only for the affinity for 5-HT_1A and D4.2 receptors but also in some cases for α _2A-adrenoceptors.

Acknowledgement

The technical assistance of Y. Abrassart, P. Fraikin, S. Counerotte, and J. Wuidart for IR spectra, ¹³C NMR measurements, elemental analyses, and mass spectra respectively is gratefully acknowledged. Supported in part by grants of the Fonds de la Recherche Scientifique FNRS (F.R.S.-FNRS) and the Fonds Spéciaux pour la Recherche of the University of Liège (Belgium). J.-F.L. is a Research Director of the F.R.S.-FNRS. This work was also supported in part by the National Institute of Mental Health Psychoactive Drug Screening Program and U19MH82441 to B.L.R.

References

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives Differentially Modulate Affinity for 5-HT1A, D4.2, and α 2A Receptors: Synthesis and In Vitro Radioligand Binding Studies

Abstract

Acknowledgement

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Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives Differentially Modulate Affinity for 5-HT_1A, D4.2, and α _2A Receptors: Synthesis and In Vitro Radioligand Binding Studies