5-HT(2C) receptor activation is a common mechanism on proerectile effects of apomorphine, oxytocin and melanotan-II in rats.

5-Hydroxytryptamine (5-HT), dopamine, oxytocin and melanocortin pathways are known to be involved in the induction of penile erections in rats. Although a dopamine-oxytocin-5-HT link in the central nervous system has been suggested to be important to the control of penile erections, the 5-HT receptor subtype that mediates dopamine-oxytocin-5-HT action and the relationship between the dopamine-oxytocin-5-HT pathway and melanocortin pathway have not been fully elucidated. In this study, in order to clarify these matters, we examined the effects of a selective 5-HT(2B)/5-HT(2C) receptors antagonist, 1-(1-methylindol-5-yl)-3-(3-pyridyl)urea (SB200646) and a selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline (SB242084) on penile erections induced by a dopamine receptor agonist, 10, 11-dihydroxyaporphine (apomorphine), oxytocin, or a melanocortin receptor agonist, melanotan-II (MT-II) in rats. SB200646 at 10 mg/kg and SB242084 at 3 mg/kg, these doses which completely antagonize penile erections induced by 5-HT(2C) receptor agonists, m-chlorophenylpiperazine (mCPP) and (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), significantly inhibited penile erections elicited by apomorphine, oxytocin or MT-II. In addition, in order to clarify further the suggestion that the 5-HT pathway projecting from medulla oblongata to lumbosacral spinal site and lumbosacral 5-HT(2C) receptor are involved in the induction of penile erection, we also examined the proerectile effect of YM348 in spinal and a 5-HT depletor, p-chlorophenyl alanine (pCPA)-treated rats. YM348 induced intracavernous pressure increase in spinal and pCPA-treated rats as well as normal rats. These results suggest that 5-HT(2C) receptor in lumbosacral spinal sites mediates not only dopamine-oxytocin-5-HT action but melanocortin action on penile erections, and that the 5-HT pathway is located downstream from melanocortin pathway as well as the dopamine-oxytocin pathway.

Synthesis and structure-activity relationships of a series of benzazepine derivatives as 5-HT2C receptor agonists.

To identify potent and selective 5-HT(2C) receptor agonists, a series of novel benzazepine derivatives were synthesized, and their structure-activity relationships examined. The compounds were evaluated for their 5-HT(2C), 5-HT(2A), and 5-HT(2B) receptor binding affinity and intrinsic activity for the 5-HT(2C) and 5-HT(2A) receptors. Among these compounds, 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine (6) was effective in a rat penile erection model when administered po, which is a symptom of the serotonin syndrome reflecting 5-HT(2C) receptor activation. Moreover, compound 6 was characterized as a partial agonist of 5-HT(2A) receptors; therefore, it had little effect on the cardiovascular system.

Synthesis and structure-activity relationships of a series of substituted 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine derivatives as 5-HT2C receptor agonists.

A series of novel indazole derivatives were synthesized, and their structure-activity relationships examined in order to identify potent and selective 5-HT2C receptor agonists. Among these compounds, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348) had a good in vitro profile, that is, high agonistic activity to the human 5-HT2C receptor subtype (EC50 = 1.0 nM) and high selectivity over 5-HT2A receptors. This compound was also effective in a rat penile erection model when administered p.o.

Characterization of intracavernous pressure increase induced by Ym348, a novel 5-HT2C receptor agonist, in anesthetized rats.

PURPOSE: We investigated the effects of the novel 5-HT2C receptor agonist YM348 [(S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine] on ICP in anesthetized rats and clarified whether behavioral changes such as hypolocomotion induced at a high dose are a cause of the inverted U-shaped PE dose-response curves in conscious rats. MATERIALS AND METHODS: Male Wistar rats (Japan SLC, Shizuoka, Japan) weighing 250 to 315 gm were used. The pro-erectile effect of YM348 (2.03 to 67.7 microg/kg subcutaneously) was examined in conscious rats. ICP was also monitored after YM348 treatment (0.677 to 67.7 mug/kg subcutaneously) in anesthetized rats. Response number, latency, duration, peak pressure and area under the curve were measured. The selective 5-HT2C receptor antagonist SB242084 [(6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline)] (0.03 to 1 mg/kg intraperitoneally) was administered 30 minutes before YM348 treatment. RESULTS: YM348 induced PE and ICP increases, and was significantly inhibited by SB242084. Dose-response curves for the number of PEs and ICP increases were an inverted U shape. YM348 decreased the latency of but did not affect the quality of ICP (duration, peak pressure and area under the curve) even at the highest dose. CONCLUSIONS: Activation of 5-HT2C receptor increased ICP and, as a result, induced PE. Since the dose-response curve for the number of ICP increases under anesthetized, behavior independent conditions still showed an inverted U shape, behavioral changes were not likely to have contributed to the inverted U-shaped dose-response curves for the number of PEs in conscious rats. Furthermore, the certain magnitude of ICP increases was likely to have occurred despite the stimulus intensity after the level of 5-HT2C receptor activation crossed the threshold.

Antiobesity effect of YM348, a novel 5-HT2C receptor agonist, in Zucker rats.

The purpose of the present study was to investigate the potency of (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), a 5-HT2C receptor agonist, as an antiobesity agent in Zucker rats. Single oral administration of YM348 at 0.1, 0.3, 1 and 3 mg/kg significantly reduced food intake in a dose-dependent manner. This effect of YM348 on food intake was inhibited by SB242084, a selective 5-HT2C receptor antagonist. In addition, single administration of YM348 significantly increased body temperature and calorie expenditure at doses of 0.3, 1 and 3 mg/kg, and 1 and 3 mg/kg p.o., respectively. The increasing effect of YM348 on body temperature and calorie expenditure was inhibited by SB242084. Chronic subcutaneous infusion of YM348 (3 and 30 mg/kg/day) for 2 weeks also decreased food intake. However, this hypophagic effect of YM348 was marked during the initial week of infusion but only minor in the second. In contrast, no diminution of effect on body temperature and calorie expenditure was seen on repeated administration of YM348 (1 mg/kg p.o.). Two weeks' subcutaneous infusion of YM348 (3 and 30 mg/kg/day) resulted in a significant decrease in body weight gain throughout the experiment. These results suggest that the maintenance of thermogenesis contributed to the reduced body weight by YM348. The ability of YM348 to decrease body weight in Zucker rats suggests its strong potential for development as an antiobesity agent in humans.

Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist.

YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, showed a high affinity for cloned human 5-HT(2C) receptors (K(i): 0.89 nM). The functional selectivity for 5-HT(2C) receptors in the 5-HT(2) receptor family was the highest among 5-HT(2C) receptor agonists, including m-chlorophenylpiperazine (mCPP) and Ro60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine). Oral administration of YM348 induced penile erections and hypolocomotion in rats, being completely inhibited by a selective 5-HT(2C) receptor antagonist, SB242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline). The dose-response curve for penile erections, unlike that for hypolocomotion, was an inverted U-shape in the dose range of 0.0677-2.03 mg/kg. A selective 5-HT(2A) receptor antagonist, MDL100907 (R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol), and a selective 5-HT(2B) receptor antagonist, RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine), had no effect on the decline in penile erection frequency at 2.03 mg/kg of YM348. YM348 did not affect blood pressure at 2.03 mg/kg. In conclusion, YM348 is a novel, potent and orally active 5-HT(2C) receptor agonist, and neither the activation of 5-HT(2A) or 5-HT(2B) receptors nor a cardiovascular effect is likely to contribute to the inverted U-shape dose-response curve for penile erections.