P. Carato et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1570–1574
1573
antipsychotics in patients with schizophrenia and other
Acknowledgments
psychotic disorders. Indeed, an involvement of D4
receptors in hippocampal neurons’ activity by depress-
ing N-methyl-D-aspartate (NMDA) receptor activity
through the activation of platelet-derived growth factor
receptors was reported.19 An inhibition of glutamatergic
signaling in the frontal cortex was also shown.20 Both
effects tend to link this receptor and the glutamate
signaling system which has been clearly associated
with cognition. The evaluation of the mixed D4/5-HT2A
ligand fananserin in schizophrenic patients was
unsuccessful.21 Nevertheless, the role of these receptors’
needs to be clarified since it has been shown that chronic
clozapine or related antipsychotics increase D4 receptors
density and decrease 5-HT2A receptor density in brain
areas involved in psychotic disorders.22–24
The technical assistance of Y. Abrassart, S. Counerotte
is gratefully acknowledged. A.G. is a Research Fellow of
`
the ‘Fonds pour la formation a la Recherche Industrielle
et Agricole (F.R.I.A.)’. J.F.L. is a Senior Research
Associate of the ‘Fonds National de la Recherche Scien-
tifique de Belgique (F.N.R.S.)’. P.C. was supported by a
`
post-doctoral fellowship of the University of Liege.
Functional data were generously provided in the context
of the National Institute of Mental Health’s Psychoac-
tive Drug Screening Program (NIMH PDSP) Contract
NO1MH32004.
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FANANSERIN
.
In summary, the naphthamides presented in this and the
previous article act as antagonists at D4.2 and 5-HT2A
receptors with highly varying selectivities. These data
will be useful in future molecular modeling studies for
the development of new CNS drugs and, finally, to in-
crease our understanding of CNS disorders.
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dez, J.; Ariano, M. A.; Falzone, T. L.; Kozell, L. B.;
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Grandy, D. K. J. Neurosci. 2001, 21, 3756.