Received for publication April 13, 2005.
Revised June 7, 2005.
Accepted for publication June 8, 2005.

Differential effects of the 5 HT1A 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

Abstract

The pharmacological properties of Rec 27/0224 (Cyclohexanecarboxylic acid {2-[4-(2-bromo-5-methoxybenzyl)piperazin-1-yl]ethyl}-(2-trifluoromethoxyphenyl)amide) and Rec 27/0074 (Cyclohexanecarboxylic acid (2-methoxy-phenyl)-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl}amide) were characterized using radioligand displacement and [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-HT_1A receptors vs 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 WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclo-hexanecarboxamide).

Key words: 5-HT1A inverse agonist, Rec 27/0074, Rec 27/0224, citalopram, dorsal raphe, hippocampus

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