QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.087809v1 315/1/109    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Corradetti, R. Articles by Testa, R. Search for Related Content PubMed PubMed Citation Articles by Corradetti, R. Articles by Testa, R.

NEUROPHARMACOLOGY

Differential Effects of the 5-Hydroxytryptamine (5-HT)_1A Receptor Inverse Agonists Rec 27/0224 and Rec 27/0074 on Electrophysiological Responses to 5-HT_1A Receptor Activation in Rat Dorsal Raphe Nucleus and Hippocampus in Vitro

Dipartimento di Farmacologia Preclinica e Clinica "Mario Aiazzi-Mancini," Università di Firenze, Florence, Italy (R.C., B.M., C.F., A.M.P.); and Pharmaceutical R&D Division—Recordati S.p.A., Milan, Italy (A.C., C.D., R.T.)

The pharmacological properties of cyclohexanecarboxylic acid, {2-[4-(2-bromo-5-methoxybenzyl)piperazin-1-yl]ethyl}-(2-trifluoromethoxyphenyl)amide (Rec 27/0224), and cyclohexanecarboxylic acid, (2-methoxy-phenyl)-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl}amide (Rec 27/0074), were characterized using radioligand displacement and guanosine 5'-O-(3-[³⁵S]thiotriphosphate) ([³⁵S]GTPS) binding assays, as well as electrophysiological experiments, in rat hippocampal and dorsal raphe nucleus (DRN) slices. Both compounds showed a high affinity (K_i, 1 nM) and selectivity (>70-fold) at human 5-hydroxytryptamine (5-HT)_1A receptors versus other 5-HT receptors. In [³⁵S]GTPS binding assays on HeLa cells stably expressing human 5-HT_1A receptors, Rec 27/0224 and Rec 27/0074 inhibited basal [³⁵S]GTPS binding by 44.8 ± 1.7% (pEC₅₀ = 8.58) and 25 ± 2.5% (pEC₅₀ = 8.86), respectively. In intracellularly recorded CA1 pyramidal cells, 5-HT_1A (hetero)receptor-mediated hyperpolarization, elicited by 100 nM 5-carboxamidoytryptamine (5-CT), was partially antagonized by Rec 27/0224 (50%; IC₅₀ = 18.0 nM) and Rec 27/0074 (74%; IC₅₀ = 0.8 nM). In extracellularly recorded DRN serotonergic neurons, Rec 27/0224 and Rec 27/0074 fully antagonized the inhibition of firing caused by the activation of 5-HT_1A (auto)receptors by 30 nM 5-CT with an IC₅₀ of 34.9 nM and 16.5 nM, respectively. The antagonism had a slow time course, reaching a steady state within 60 min. Both compounds also antagonized the citalopram-elicited, endogenous 5-HT-mediated inhibition of cell firing. In conclusion, Rec 27/0224 and Rec 27/0074 exhibited inverse agonism in [³⁵S]GTPS binding assays and differential antagonistic properties on 5-HT_1A receptor-mediated responses in the hippocampus but not in the DRN. Whether this differential effect is causally related to inverse agonist activity is unclear. The qualitatively different nature of the antagonism in the hippocampus versus the DRN clearly distinguishes the compounds from neutral antagonists, such as N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclo-hexanecarboxamide (WAY-100635).

Address correspondence to: Dr. Renato Corradetti, Dipartimento di Farmacologia Preclinica e Clinica "Mario Aiazzi-Mancini," Università di Firenze, V.le G. Pieraccini 6, 50139 Florence, Italy. E-mail: corradet{at}unifi.it

This article has been cited by other articles:

				J.-C. Martel, A.-M. Ormiere, N. Leduc, M.-B. Assie, D. Cussac, and A. Newman-Tancredi Native Rat Hippocampal 5-HT1A Receptors Show Constitutive Activity Mol. Pharmacol., March 1, 2007; 71(3): 638 - 643. [Abstract] [Full Text] [PDF]