WAY 161503 hydrochloride

Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties.[Pubmed:23301527]

J Med Chem. 2013 Feb 14;56(3):1211-27.

The isoxazol-3-one tautomer of the bicyclic isoxazole, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol (THAZ), has previously been shown to be a weak GABA(A) and glycine receptor antagonist. In the present study, the potential in this scaffold has been explored through the synthesis and pharmacological characterization of a series of N- and O-substituted THAZ analogues. The analogues N-Bn-THAZ (3d) and O-Bn-THAZ (4d) were found to be potent agonists of the human 5-HT(2A) and 5-HT(2C) receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the 3d analogue appears to be selective for the two receptors. Administration of 3d substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT(2C) antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most likely mediate their effects through 5-HT(2A) and/or 5-HT(2C) receptors, the isoxazoles 3d and 4d constitute interesting leads for further medicinal chemistry development.

Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine(2C) receptors.[Pubmed:11082448]

J Pharmacol Exp Ther. 2000 Dec;295(3):1120-6.

The role of the 5-HT(2C) receptor in mediating active behaviors in the modified rat forced swim test was examined. Three novel selective 5-HT(2C) receptor agonists, WAY 161503 (0.1-3.0 mg/kg), RO 60-0175 (2-20 mg/kg), and RO 60-0332 (20 mg/kg), all decreased immobility and increased swimming, a pattern of behavior similar to that which occurs with the selective serotonin reuptake inhibitor fluoxetine (5-20 mg/kg). However, the prototypical but nonselective 5-HT(2C) receptor agonist m-chlorophenylpiperazine (1-10 mg/kg) increased immobility scores in the forced swim test. The selective 5-HT(2C) receptor antagonist SB 206533 was inactive when given alone (1-20 mg/kg). However, SB 206533 (20 mg/kg) blocked the antidepressant-like effects of both WAY 161503 (1 mg/kg) and fluoxetine (20 mg/kg). The atypical antidepressant (noradrenergic alpha(2) and 5-HT(2C) receptor antagonist) mianserin reduced immobility and increased climbing at 30 mg/kg. At a behaviorally subactive dose (10 mg/kg), mianserin abolished the effects of WAY 161503 (1 mg/kg) on both swimming and immobility scores. Mianserin blocked the effects of fluoxetine (20 mg/kg) on swimming only; mianserin plus fluoxetine reduced immobility and induced a switch to climbing behavior, suggesting activation of noradrenergic transmission. These data exemplify the benefits of using the modified rat forced swim test, which was sensitive to serotonergic compounds and distinguished behavioral changes associated with serotonergic and noradrenergic effects. Taken together, the results strongly implicate a role for 5-HT(2C) receptors in the behavioral effects of antidepressant drugs.

Synthesis and 5-hydroxytryptamine (5-HT) activity of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines.[Pubmed:10987434]

Bioorg Med Chem Lett. 2000 Sep 4;10(17):1991-4.

A series of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines was shown to exhibit 5-HT2C agonist binding and functional activity. Compound 21R inhibited food intake over 2 h in fasted, male Sprague Dawley rats with ED50 values of 2 mg/kg (i.p.) and 10 mg/kg (p.o.).