Disease relevance of LS-172058

• The doses of SR 46349 which inhibited 50% of thrombus formation were 1.5 +/- 0.8 mg/kg and 17 +/- 0.5 mg/kg after i.v. or oral administration respectively [1].

Psychiatry related information on LS-172058

• Behavioral experiments, including mescaline- and 5-hydroxytryptophan-induced head twitches and learned helplessness, as well as sleep-waking cycle and EEG spectral parameter studies, indicated that SR 46349B has a classical 5-HT2 psychopharmacological antagonist profile [2].

High impact information on LS-172058

• These results indicate that SR 46349B increases 5-HT2 receptor binding and functions without altering steady-state 5-HT2 mRNA levels in cultured rat aortic smooth muscle cells [3].
• Adaptive changes in 5-hydroxytryptamine (5-HT)2 receptors were investigated in mice after repeated administration of SR 46349B, a potent, selective, and competitive 5-HT2 receptor antagonist (Kl = 0.72 +/- 0.05 nM) [4].
• These results show that repeated administration of SR 46349B produced a parallel enhancement in 5-HT2 receptor number, in 5-HT2 receptor-linked signal transduction, and in 5-HT2 receptor-mediated behavioral responses in mice [4].
• Further, administration of the 5-HT2 agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane produced, in SR 46349B (10 mg/kg, orally)-treated mice, a significant stimulation of the 5-HT2 receptor-linked phosphoinositide turnover in vivo in the brain [4].
• To investigate the effect on the sleep EEG, a 1-mg oral dose of SR 46349B, a novel 5-HT2 antagonist, was administered three hours before bedtime [5].

Biological context of LS-172058

• Significant increase of the bleeding time was observed after the i.v. administration of 5 mg/kg of SR 46349 (3-fold increase) [1].
• A single per os administration of SR 46349 (1 mg/kg) resulted in a strong inhibition of 5-HT+epinephrine-induced platelet aggregation in the rabbit as measured ex vivo (67% inhibition, 6 h after the administration) [1].
• Up-regulation of 5-HT2 receptors in the rat brain by repeated administration of SR 46349B, a selective 5-HT2 receptor antagonist [6].
• Identification of binding sites for SR 46349B, a 5-hydroxytryptamine2 receptor antagonist, in rodent brain [7].

Anatomical context of LS-172058

• Regulation of 5-hydroxytryptamine2 (5-HT2) receptor expression in cultured rat aortic smooth muscle cells by SR 46349B, a selective 5-HT2 receptor antagonist [3].
• Repeated administration (twice per day for 3 days and once on the morning of the fourth day) of SR 46349B (5 or 10 mg/kg, orally) caused 24 hr later a marked increase in 5-HT2 receptor number (+41% and +75%, respectively), measured ex vivo in brain cortical membranes with [3H] ketanserin, without affecting its affinity constant [4].
• In dogs, SR 46349 inhibited cyclic coronary artery blood flow variations, complete abolition of CFVs being achieved after the i.v. administration of 0.5 mg/kg [1].
• Based upon binding studies with 5-HT2 receptors in rat brain cortical membranes and blockade of 5-HT-induced contractions in isolated tissues (rabbit thoracic aorta, rat jugular vein, rat caudal artery, rat uterus and guinea pig trachea), SR 46349B showed high affinity for 5-HT2 receptors [2].

Associations of LS-172058 with other chemical compounds

• Regulation of 5-hydroxytryptamine (5-HT2) receptor expression by SR 46349B, a potent and selective 5-HT2 receptor antagonist, was investigated in cultured rat aortic smooth muscle cells [3].
• SR 46349 (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorophe nyl) propen-1-yl] phenol, hemifumarate) is the first member of a newly-developed 5-HT2 antagonist series [1].
• In contrast, the selective 5-HT2A receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages [8].
• Furthermore, SR 46349B displayed moderate affinity for the 5-HT1C receptor and had no affinity for the other 5-HT1 subclass (5-HT1A, 5-HT1B or 5-HT1D), dopamine (D1 or D2), "alpha" adrenergic (alpha-1 or alpha-2), sodium and calcium channel and histamine (H1) receptors [2].
• The intermediate degree of [-]-DOM generalization to nefazodone was significantly antagonized by the 5-HT antagonists, 5-HT2, SR 46349B (5HT2A/2C), and M100907 (5-HT2A) [9].

Gene context of LS-172058

• This effect was reversed by the 5-HT2B/2C receptor antagonist as did SR 46349B, for both doses administered [8].
• A new potent, selective and p.o. active serotonergic [5-hydroxytryptamine (5-HT2)] receptor antagonist, SR 46349B [trans, 4-([3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-flurophenyl++ +)propen-1-yl]phenol hemifumarate) has been characterized by a series of "in vitro" and "in vivo" methods [2].
• As was expected, the selective 5-HT2A/C antagonist, SR 46349B, did not affect the intensity 8-OH DPAT-induced symptoms [10].
• Based upon blockade of pressor responses to 5-HT in pithed rats and in vivo binding studies in mice, SR 46349B was found to be a potent and p.o. active 5-HT2 receptor antagonist with a relatively long duration of action [2].

Analytical, diagnostic and therapeutic context of LS-172058

• Additionally, in vivo microdialysis studies were performed in awake freely moving rats using similar pharmacologic challenges plus SR 46349B, a new highly selective 5-HT2 receptor antagonist [11].
• Neither SR 46349B (0.25-1 mg/kg) nor SDZ SER-082 (0.25-1 mg/kg) altered the maintenance of cocaine self-administration [12].

References