Shigenori Ohkawa

Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist.

Ramelteon (TAK-375) is a novel melatonin receptor agonist currently under investigation for the treatment of insomnia. This study describes the neurochemical and receptor binding characteristics of ramelteon in vitro. Ramelteon showed very high affinity for human MT1 (Mel1a) and MT2 (Mel1b) receptors (expressed in Chinese hamster ovary [CHO] cells), and chick forebrain melatonin receptors (consisting of Mel1a and Mel1c receptors) with Ki values of 14.0, 112, and 23.1 pM, respectively, making the affinities of ramelteon for these receptors 3-16 times higher than those of melatonin. The affinity of ramelteon for hamster brain MT3 binding sites was extremely weak (Ki: 2.65 microM) compared to melatonins affinity for the MT3 binding site (Ki: 24.1 nM). In addition, ramelteon showed no measurable affinity for a large number of ligand binding sites (including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters) and no effect on the activity of various enzymes. Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors. Taken together, these results indicate that ramelteon is a potent and highly selective agonist of MT1/MT2 melatonin receptors.

Coronary vasoconstriction and PGI2 release by leukotrienes in isolated guinea pig hearts

In isolated, perfused guinea pig hearts, leuokotrienes C4 and D4 (0.1–100 ng) dose-dependently decreased coronary flow rate and left ventricular systolic pressure. The leukotrienes (10–100 ng) released prostacyclin, but not thromboxane A2, from the heart. In isolated atria, they (10−8–10−6 M) showed slight positive inotropism. Thus, it is concluded that leukotrienes C4 and D4 are potent coronary vasoconstrictors, and might play a role in coronary vasospasm during cardiac anaphylaxis.

Ramelteon (TAK-375) Accelerates Reentrainment of Circadian Rhythm after a Phase Advance of the Light-Dark Cycle in Rats

In vivo pharmacological effects of ramelteon (TAK-375), a novel, highly MT1/MT2-selective receptor agonist, were studied in rats to determine ramelteon’s ability to reentrain the circadian rhythm after an abrupt phase advance. Experiments were also conducted to assess the potential cognitive side effects of ramelteon and its potential to become a drug of abuse. After an abrupt 8-h phase shift, ramelteon (0.1 and 1 mg/kg, p.o.) and melatonin (10 mg/kg, p.o.) accelerated reentrainment of running wheel activity rhythm to the new lightdark cycle. Ramelteon (3-30 mg/kg, p.o.) and melatonin (10-100 mg/kg, p.o.) did not affect learning or memory in rats tested by the water maze task and the delayed match to position task, although diazepam and triazolam impaired both of the tasks. Neither ramelteon (3-30 mg/kg, p.o.) nor melatonin (10-100mg/kg, p.o.) demonstrated a rewarding property in the conditioned place-preference test, implying that MT1/MT2 receptor agonists have no abuse potential. In contrast, benzodiazepines and morphine showed rewarding properties in this test. The authors’ results suggest that ramelteon may be useful for treatment of circadian rhythm sleep disorders without adverse effects typically associated with benzodiazepine use, such as learning and memory impairment, and drug dependence.

Effects of ramelteon (TAK-375) on nocturnal sleep in freely moving monkeys.

We investigated the effects of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4]furan-8-yl)ethyl]propionamide (ramelteon, TAK-375), a novel MT1/MT2 receptor agonist, on nocturnal sleep in freely moving monkeys and compared these results with those of melatonin and zolpidem. Treatment with ramelteon (0.03 and 0.3 mg/kg, p.o.) significantly shortened latency to sleep onset and significantly increased total duration of sleep. Treatment with melatonin (0.3, 1, and 3 mg/kg, p.o.) also decreased sleep latency, but the effect was weak; the only significant reduction was seen with the 0.3 mg/kg dose on latency to light sleep. Melatonin had no significant effects on the duration of sleep. Zolpidem had no significant effects on latency to sleep onset in this study at any dose (1, 3, 10, and 30 mg/kg, p.o.). The highest dose (30 mg/kg) of zolpidem had a tendency to increase slow wave sleep; however, it also induced apparent sedation and myorelaxation. Treatment with ramelteon and melatonin had no evident effect on the general behavior of the monkeys. Spectral analysis (fast Fourier transform, FFT) of both ramelteon and melatonin revealed sleep patterns that were indistinguishable from those of naturally occurring sleep. The EEG power spectra of zolpidem were qualitatively different from that of naturally occurring physiological sleep. Results of the present study support the investigation of ramelteon as a sleep-promoting agent in humans.

Contractile activities of leukotrienes C4 and D4 on vascular strips from rabbits

Abstract Leukotrienes C4 (LTC4) and D4 (LTD4), major components of slow-reacting substances of anaphylaxis (SRS-A), caused dose-dependent contractions of rabbit coronary arteries in concentrations of 10−9 to 10−7 M and 10−10 to 10−7 M, respectively. The potency of LTC4 and LTD4, when compared with the concentration that elicits half of the contraction induced by 25 mM KCl, was 17 and 76 times, respectively, greater than that of histamine. In contrast, other blood vessels from rabbits were either unresponsive (renal artery and vein, mesenteric artery and thoracic aorta) or only weakly responsive (pulmonary artery and vein and portal vein) to both leukotrienes even at 10−7 M. The LTD4-induced coronary contraction was inhibited by FPL 55712 (10−7 and 10−6 M), a selective SRS-A inhibitor, in a dose-dependent manner, but not by diphenhydramine (10−7 M), a histamine H1-receptor blocker or by indomethacin (10−5 M), a prostaglandin synthetase inhibitor, suggesting that LTD4 has a direct effect on the coronary arteries. These results indicate that the leukotrienes may act as potent, selective coronary vasoconstrictors and that SRS-A responsive receptors exist in the rabbit coronary artery.

Kinetic Resolution of an Indan Derivative Using Bacillus sp.SUI-12 : Synthesis of a Key Intermediate of the Melatonin Receptor Agonist TAK-375

The chiral indan derivative (S)-2 (2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl-amine) was synthesized by enzyme-catalyzed asymmetric hydrolysis of the racemic acetamide 1 (N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide). The reaction was carried out using Bacillus sp. SUI-12 screened for the ability to hydrolyze 1 to give (S)-2 with high enantioselectivity. In a scaled-up experiment, a low reaction rate was observed. However, by changing the culture medium and the reaction conditions, it became possible to run the reaction to 40% conversion on a 10-g or more scale, obtaining (S)-2 at >;99% enantiomeric excess (ee). The (S)-2 obtained was available for the synthesis of the melatonin receptor agonist TAK-375 (N-[2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propanamide).

Synthesis of TAK-218 using (R)-2-methylglycidyl tosylate as a chiral building block

Abstract We performed an asymmetric synthesis of ( S )-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine dihydrochloride (TAK-218, 1 ), a compound used for the treatment of traumatic and ischemic central nervous system injuries. Oxirane 6 , which was synthesized from ( R )-2-methylglycidyl tosylate, was treated with aqueous trifluoroacetic acid to afford benzofuranmethanol 7 with inversion of stereochemistry at the stereogenic center. Compound 7 was converted into 1 with high enantiomeric excess in four steps.

Quinones. Part 2. General synthetic routes to quinone derivatives with modified polyprenyl side chains and the inhibitory effects of these quinones on the generation of the slow reacting substance of anaphylaxis (SRS-A)

General synthetic routes to quinone acids (8), quinone amides (9), quinone alcohols (10), and quinone methylketones (11) with polyprenyl side chains, in which allylic alcohols (3) are employed as the key intermediates, are described. The Claisen rearrangements and the Carrot reactions of the allylic alcohols (3) with ethyl orthoacetate and diketen produced the ethyl esters (4) and the methylketones (5), respectively. Quinone products (8), (10), and (11) were recovered by oxidative demethylation of hydroquinone dimethyl ethers (4), (5), and (7) or by acid hydrolysis of hydroquinone bis(methoxymethyl) ethers (4) and (5) followed by ferric chloride oxidation. Amidation of quinone acids (8) led to the formation of quinone amides (9). Inhibitory effects of these quinone derivatives on the generation of the slow reacting substance of anaphylaxis (SRS-A) in the lungs of sensitised guinea pigs are evaluated.

Kinetic Resolutions of Indan Derivatives Using Bacteria

Racemic indan derivatives have been resolved by the hydrolysis of amide bonds using Corynebacterium ammoniagenes IFO12612 to produce (S)-amine and (R)-amides. In the kinetic resolution of 1 (N-[2-(6-methoxy-indan-1-yl)ethyl]acetamide), it was possible to run the reaction to 44% conversion on a 10-g scale, obtaining (S)-amine 4 ((S)-2-(6-methoxy-indan-1-yl)ethylamine) at >99% enantiomeric excess (ee) and (R)-1 at 98% ee.