Biochemical and electrophysiological properties of SR 57746A, a new, potent 5-HT1A receptor agonist.
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.
Bachy
A
A
Sanofi Recherche, Toulouse, France.
Steinberg
R
R
Santucci
V
V
Fournier
M
M
Landi
M
M
Hamon
M
M
Manara
L
L
Keane
P E
PE
Soubrié
P
P
Le Fur
G
G
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000588:Amines / Q000378:metabolism; D000818:Animals; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000201:enzymology; D009281:Naphthalenes / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology; D014316:Tritium; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
D000588:Amines; D009281:Naphthalenes; D011725:Pyridines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014316:Tritium; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases; C462299:xaliproden