Novel piperazines: potent melanocortin-4 receptor antagonists with anxiolytic-like activity.

In the present study, we found that a novel piperazine compound, 11a, showed a moderate affinity (IC(50)=333nM) for the MC4 receptor. We developed the new type of piperazine compounds and found that mono-piperazine 11b exhibited a high-affinity (IC(50)=40.3nM) for the MC4 receptor. We also found that a series of biphenyl analogues exhibited a high-affinity for the receptor, and in particular, compound 11j exhibited the highest affinity for the MC4 receptor with an IC(50) value of 14.5nM. Furthermore, some of these compounds, when administered orally, significantly reversed the stress-induced anxiety-like behavior in rats. In this paper, we report the synthesis, structure-activity relationships, and oral activity of the novel mono-piperazines as MC4 receptor antagonists.

In vitro and antinociceptive profile of HON0001, an orally active NMDA receptor NR2B subunit antagonist.

The analgesic activity and side effect liabilities of a novel NR2B antagonist, 7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (HON0001) were investigated. HON0001 inhibited [3H]MK-801 binding to rat brain membranes in a biphasic manner, with IC50 values of 54.68+/-4.96 nM and 46.48+/-5.85 muM for high- and low-affinity sites, respectively. HON0001 inhibited [3H]ifenprodil binding to membranes of rat cerebral cortex with an IC50 value of 57.01+/-3.4 nM, consistent with the results obtained for high-affinity sites of [3H]MK-801 binding. HON0001 exhibited no or negligible affinity for other receptors, transporters and ion channels, while HON0001 had a moderate agonistic activity at mu-opioid receptors and affinity for dopamine D1 receptors. HON0001 exhibited an analgesic effect in carrageenan-induced mechanical hyperalgesia and in the Seltzer model of partial sciatic nerve ligation following oral administration. In contrast, unlike MK-801, HON0001 did not affect spontaneous locomotor activity, rotarod performance and step-through latency in a passive avoidance task even at doses much higher than antinociceptive doses. HON0001 exhibited excellent brain penetration with a brain-to-plasma ratio of 34.5. These findings show that HON0001 is an orally active NR2B antagonist and that it may be useful for treating patients with neuropathic and other conditions without causing the side effects often observed with currently available non-subtype selective NMDA receptor antagonists.

Antipsychotic action of selective group II metabotropic glutamate receptor agonist MGS0008 and MGS0028 on conditioned avoidance responses in the rat.

The present study was designed to investigate the antipsychotic-like effects of selective group II metabotropic glutamate receptor (mGluR) agonists, 5-[2-[4-(6-fluoro-1H-indole-3-yl) piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide (MGS0008) and (1R, 2S, 5S, 6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate (MGS0028) on conditioned avoidance responses in rats. MGS0008 (1, 3 and 10 mg/kg, p.o.) and MGS0028 (0.3, 1 and 3 mg/kg, p.o.) significantly and reduced conditioned avoidance responses in a dose-dependent fashion. Similar effects were seen with LY418426 (0.3, 1 and 3 mg/kg, p.o.), but not with LY354740 (3, 10 and 30 mg/kg, p.o.), both of which are selective agonists for group II mGluR. Since this effect is seen with a wide range of antipsychotics, such as haloperidol and clozapine [Life Sciences 71 (2002) 947], group II mGluR agonists deserve further attention for possible antipsychotic activity.

Antipsychotic profile of 5-[2-[4-(6-fluoro-1H-indole-3-yl)piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide (NRA0562) in rats.

The antipsychotic profile of 5-[2-[4-(6-fluoro-1H-indole-3-yl)piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide (NRA0562) was investigated using the conditioned avoidance test in rats. NRA0562 is a putative "atypical" antipsychotic agent with moderate to high affinities for dopamine D(1), D(2), D(4), 5-hydroxytryptamine(2A) receptors and alpha(1) adrenoceptor. NRA0562 (1 and 3 mg/kg, p.o.) dose-dependently and significantly impaired the conditioned avoidance response. Likewise other atypical antipsychotics such as risperidone (1 and 3 mg/kg, p.o.) and clozapine (100 mg/kg, p.o.) dose-dependently and significantly impaired the conditioned avoidance response in rats. In addition, typical antipsychotics, haloperidol (1 and 3 mg/kg, p.o.) potently impaired the conditioned avoidance response.These results suggest that antipsychotic profile of NRA0562 is consistent with profiles of clozapine or risperidone and may be considered an atypical antipsychotic agent.