Biochemical and electrophysiological properties of SR 57746A, a new, potent 5‐HT_1A receptor agonist

Abstract

SR 57746A (1-[2-(naphth-2-yl) ethyl]-4-(3-trifluoromethylphenyl)-1, 2, 5, 6 tetra-hydropyridine hydrochloride) binds competitively, and with high affinity (Ki = 2.0 +/- 0.7 nM) to 5-HT1A receptors from rat hippocampus in vitro, but has much less affinity for other 5-HT receptor subtypes (IC50 > 650 nM). SR 57746A produces a concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates, with a maximal effect identical to that of 8-OH-DPAT, suggesting that SR 57746A behaves as a full agonist in this experimental model. SR 57746A potently displaces [3H]8-OH-DPAT binding to rat hippocampal membranes ex vivo, with an ID50 of 11.1 mg/kg po, 30 min after administration, and 2.8 mg/kg po, 2 h after administration. This effect of SR 57746A is long-lasting (at least 24 hours at 10 mg/kg po). SR 57746A does not modify the levels of 5-HT or DA in various brain areas, but decreases the concentrations of 5-HIAA, and increases those of DOPAC, HVA and 3-MT. Following i.v. administration, SR 57746A (0.095 to 0.25 mg/kg) inhibits the spontaneous firing of dorsal raphe neurones, but does not modify the activity of DA neurones in the substantia nigra or ventral tegmental area. Thus, SR 57746A is a potent, selective and full agonist at 5-HT1A receptors in vitro and vivo.

Effect of the neuroprotective compound SR57746A on nerve growth factor synthesis in cultured astrocytes from neonatal rat cortex

“…SR57746A has no a nity for the majority or neurotransmitter receptors except for the 5-HT 1A receptor for which this compound is a potent agonist (Bachy et al, 1993). As shown in the present study, the compound's e ects were not shared by 8-OH-DPAT, suggesting that the 5-HT 1A receptor is not involved in, or is not su cient by itself, to induce the neurotrophin-promoting e ect of SR57746A.…”

“…In contrast, 6 h of IL-1 (10 U ml 71 ) incubation induced signi®cant increases of NGF mRNA (280% of control) and BDNF mRNA (206% of control; Table 1). While SR57746A has no or only very low a nity for the majority of neurotransmitter receptors, including bnoradrenergic receptors, whose stimulation can increase NGF production in cortical astrocytes (Schwartz & Mishler, 1990), the compound is a potent agonist for the 5HT 1A receptor (Bachy et al, 1993). The e ect of the 5HT 1A receptor agonist 8-OH-DPAT was therefore evaluated on neurotrophin mRNA levels in astrocyte cultures.…”

“…In a variety of experimental models, this compound elicits activities similar to those of neurotrophic factors, and particularly of nerve growth factor (NGF) (see Fournier et al, 1993). In vitro, SR57746A increases neurite elongation and survival of rat foetal septal cultures and potentiates the e ect of NGF on neurite outgrowth in PC12 cells.…”

“…The non-peptide compound, SR57746A, has been found to possess a number of neurotrophic properties in vitro and in vivo (Fournier et al, 1993;Pradines et al, 1995). In a variety of experimental models, this compound elicits activities similar to those of neurotrophic factors, and particularly of nerve growth factor (NGF) (see Fournier et al, 1993).…”

Mapk Activation Via 5-Hydroxytryptamine 1A Receptor is Involved in the Neuroprotective Effects of Xaliproden

“…Screening studies have shown that Xaliproden has high affinity for 5-hydroxytryptaminergic 5-HT1i\receptors (4,8,9). These receptors are coupled, via specific G /G o proteins, to inhibitory pathways (inhibition of adenyl cyclase (AC) activity and regulation of ion channels), and also stimulate phospholipase C (PLC) and the mitogen-activated protein kinase (MAPK) (10).…”