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The therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors in central nervous system-related diseases has attracted attention worldwide. However, the availability of reversible-type inhibitor is still limited to clarify the pharmacological effect. Herein, we report the discovery of novel spiro chemical series as potent and reversible MAGL inhibitors with a different binding mode to MAGL using Arg57 and His121. Starting from hit compound 1 and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like 2a (azetidine-lactam), 2b (cyclobutane-lactam), and 2d (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl moiety in 1 with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded 4f as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC50 6.2 nM), good oral absorption, blood-brain barrier penetration, and significant pharmacodynamic changes (2-arachidonoylglycerol increase and arachidonic acid decrease) at 0.3-10 mg/kg, po. in mice.

N-Methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has recently attracted attention as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy. In the present study, we developed potent and brain-penetrable GluN2A-selective positive allosteric modulators. Lead compound 2b was generated by scaffold hopping of hit compound 1, identified from the internal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-focused compound library through a high-throughput screening campaign. Subsequent optimization of the lead compound, including a structure-based drug design approach, resulted in the identification of a potent GluN2A PAM (R)-9, which possessed high selectivity against both subtypes of AMPAR and NMDAR. Furthermore, (R)-9 significantly enhanced long-term potentiation in the rat hippocampus 24 h after oral administration, indicating that this molecule is a potentially useful in vivo pharmacological tool for treating psychiatric diseases.

To develop higher efficiency and lower emission gasoline engines, ultra-lean burning under high Reynolds number conditions is desired. It is believed that enhancement of tumble flow in the engine cylinder is effective for increase of turbulent intensity, resulting in improvement of characteristics of flame propagation and ignition under a strong discharge, while the enhancement of tumble flow might cause heat loss from the wall. Investigations of characteristics of turbulence and distributions of wall and gas temperature in engine cylinders are still challenging due to transient and high pressure, and due to cycle-to-cycle variations. In the previous study (Jainski et al., 2013), a micro particle image velocimetry (micro PIV) measurements were conducted in an engine cylinder at up to 1100 rpm and the characteristics of velocity boundary layer around a cylinder head were investigated. The study has shown that the log-law does not properly present the measured velocity distributions near the wall. In our previous study (Shimura et al., 2018), a micro PIV was conducted in a motored engine cylinder to investigate velocity boundary layer characteristics near piston top before the top dead center (TDC) at a constant engine speed of 2000 rpm to deepen understanding characteristics of velocity boundary layer in engine cylinder with tumble flow. The velocity boundary layer was well fitted to the Blasius theory at 30 CAD before TDC and deviated from the theory at 15 CAD before TDC. However, the obtained data was two components of velocity in the measurement plane, which means that effects of magnitude of velocity were not clear in the previous measurement. In this study, stereoscopic micro PIV was conducted to elucidate the effects of magnitude and direction of velocity on the characteristics of velocity boundary layer near the piston top in the tumble enhanced SI IC optical engine. The tumble enhanced SI IC optical engine used in the previous study (Shimura et al., 2018; Matsuda et al., 2019) was used also in this study. The bore is 75 mm and the stroke is 112.5 mm. Length of the connecting rod is 250 mm. The engine has two intake valves of the diameter 29 mm and two exhaust valves of the diameter 25 mm. The compression ratio is 13.0. The optical access is achieved through the quartz glass cylinder. A tumble enhancing intake port is used for the sake of improvement of ignition and flame propagation. The engine speed can be set up to 2000 rpm at the maximum. The overall flow fields taken by a preliminary PIV experiment can be seen in the literatures (Shimura et al., 2018; Matsuda et al., 2019). The laser beams for PIV are from two Nd:YAG lasers (LOTIS, LS-2131, 150 mJ/pulse, 532 nm) are led to the same optical axis by a mirror and a polarizing beam splitter. The laser beam is formed into laser sheet of 180 µm thickness by laser sheet forming optics and led into the engine cylinder. The scattering light was collected by long distance microscope lenses (Quester, SZM100) and imaged onto CCD cameras (Princeton Technology, ES4020) in the stereoscopic alignment with 18 degrees. To compensate for the difference in the focal length caused by the quartz engine liner, a cylindrical lens of 1000 mm focal length was placed in front of each long distance microscope lens. SiO2 of 1 µm mean diameter was used for tracer particles. The micro PIV was operated at about 6.6 Hz to be synchronized with engine speed. The time separation of the successive particle images was 1.5 µs. The field of view of the micro PIV was 3.5 mm × 3.5 mm on the piston top including central axis of the cylinder. Here, x and y coordinates are set to the direction from the exhaust to the intake valves and the direction from the piston to the pent roof, respectively. z coordinates is perpendicular to x and y axes, and the orizin of the coordinates is set at the center of the piston top. The spatial resolution of PIV, which is defined by the size of interrogation region, is 108.8 µm × 54.4 µm. Vector spacing is 54.4 µm × 27.2 µm. The first vector position is about 27.2 µm away from the wall. The measurements were conducted at 345 CAD. The engine was motored at 2000 rpm and operated for three intake valve open timings of -30 CAD. The operation condition of the engine tested contain strong cycle-to-cycle variations, which results in the large root-mean-square values of velocity fluctuation near the center of the piston top (Shimura et al., 2018). To evaluate flow characteristics in the cycle-to-cycle variations, conditional averaging based on magnitude of fluid velocity is used in this study. Figure 1(a) shows a histogram of the magnitude of combined velocity of u and w. The magnitude of velocity can be considered as momentum of fluid because few fluctuation of density is considered and temperature boundary layer is enough thin compared to the velocity boundary layer. The large variations in the momentum can be observed in Fig. 1(a). The large variations are considered to be caused by the variations of tumble core locations. The fraction of the large momentum Here, the momentum are classified into C1 to C4 based on fractions (C1: 54.4%, C2: 19.5%, C3: 19.5%, C4: 6.6%). Figure 1(b) and (c) shows mean velocity distribution classified into C1 and C4 in Fig. 1(a). The distribution is fitted to the log-law velocity profile of developed wall turbulence. The mean velocity profile for C1 shows large discrepancy from that of general turbulent boundary layers, while that for C4 show relatively close to that of general turbulent boundary layer. C2 and C3, which are not shown here, have trend between the C1 and C4 profiles. These results show that the velocity profiles which can be assumed to be the developed turbulent boudary layer in the targeted condition is less than half of cycles, which means partial applicability of conventional CFD models for prediction of boundary layer of the engine condition.

The therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors in central nervous system-related diseases has attracted attention worldwide. However, the availability of reversible-type inhibitor is still limited to clarify the pharmacological effect. Herein, we report the discovery of novel spiro chemical series as potent and reversible MAGL inhibitors with a different binding mode to MAGL using Arg57 and His121. Starting from hit compound

Diffusion sensors for nano-sized materials dispersed in a solution are promising tools for investigating intermolecular interactions, which is an important task in a wide range of industrial and biomedical fields, such as the development of therapeutic products and diagnostic tools. For the development of the sensor applicable to point-of-care testing, an optofluidic sensor was proposed. The proposed sensor realizes a simple measurement in a short time using microscale manipulation by interferometrically-induced dielectrophoresis and optical detection. In this paper, the applicability of the proposed sensor to distinguish nanoscale differences in size was confirmed by measurements on a solution containing size-certified plain nano-beads (51 nm, 100 nm, 203 nm, 216 nm and 240 nm) with evaluating the uncertainties of the proposed sensor. Furthermore, measurements using 200-nm beads coated with functional groups (NH2 and biotin) and proteins (streptavidin and bovine serum albumin) demonstrated the applicability to the investigation of intermolecular interactions.

γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimer’s disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives was discovered and characterized as GSMs. Optimization of substituents at the 8-position of the core scaffold using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs. Phenoxy compound (R)-17 exhibited especially high LLE as well as potent in vivo Aβ42-lowering effect by single administration. Furthermore, multiple oral administration of (R)-17 significantly reduced soluble and insoluble brain Aβ42, and ameliorated cognitive deficit in novel object recognition test (NORT) using Tg2576 mice as an AD model.

Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early onset of Alzheimer's disease (AD). These proteins comprise the catalytic domain of γ-secretase, which catalyzes the cleavage of β-amyloid (Aβ) from amyloid precursor protein (APP). In recent reports, PS1 and PS2 were linked to the modulation of intracellular calcium ion (Ca(2+)) dynamics, a key regulator of synaptic function. Ca(2+) dysregulation and synaptic dysfunction are leading hypothesis of cognitive dysfunctions during aging and AD progression. Accordingly, manipulations of presenilins by small molecules may have therapeutic potential for the treatment of cognitive dysfunction. In an accompanying report, we showed that chronic treatment with compound-1, a novel γ-secretase modulator (GSM), reduced Aβ production and ameliorated cognitive dysfunction in Tg2576 APP transgenic mice. Accordingly, in the present study we showed that single oral administration of compound-1 at 1 and 3mg/kg ameliorated cognitive dysfunction in aged non-transgenic mice. Moreover, compound-1 enhanced synaptic plasticity in hippocampal slices from aged C57BL/6J mice and increased messenger RNA (mRNA) expression of the immediate early gene c-fos, which has been shown to be related to synaptic plasticity in vivo. Finally, compound-1 modulated Ca(2+) signals through PS1 in mouse embryonic fibroblast cells. Taken together, compound-1 ameliorates both Aβ pathology and age-related cognitive dysfunctions. Hence, compound-1 may have potential as an early intervention for the cognitive declines that are commonly diagnosed in aged subjects, such as mild cognitive impairment (MCI) and prodromal AD.

Previous studies of γ-secretase inhibitors (GSIs) and Notch-sparing GSIs have shown reduced amyloid-β (Aβ) peptide levels but increased Notch-related and -unrelated adverse effects. In this study, we examined the effects of compound-1 on Aβ processing and cognitive function and assessed Notch-related and -unrelated adverse effects. Compound-1 reduced Aβ40 and Aβ42 levels but inversely increased Aβ37 in Neuro2a cells, leading to no net changes in total Aβ levels, indicating that compound-1 is a γ-secretase modulator (GSM). In time-course experiments, compound-1 reduced Aβ40 and Aβ42 levels in tris-soluble fractions, with peak reduction at approximately 3h after oral administration in C57BL mice. Moreover, at >1mg/kg, compound-1 dose dependently reduced Aβ40 and Aβ42 levels in Tg2576 mice. Chronic treatment with compound-1 in Tg2576 mice for 4 months significantly reduced both soluble and insoluble Aβ42 levels and ameliorated cognitive impairments, even after drug withdrawal for 10 days following oral administration for 2 months. In contrast with compound-1, at 100-fold higher doses (100mg/kg), the GSI LY450139 decreased HES1 mRNA expression in thymus tissues and increased the intensity of periodic acid-Schiff (PAS)-positive areas in the intestine. Moreover, the Notch-sparing GSI BMS708163 led to amyloid precursor protein (APP)-β-C-terminal fragment accumulation in mouse primary neurons. BMS708163 significantly hampered cognitive function in normal mice 1 month after administration, whereas compound-1 significantly improved cognitive function. Taken together, the present novel and orally active GSM is a promising molecule for the treatment of pathologies associated with Aβ42 and Aβ40.

A novel plastic based microfluidic chip for the optical diffusion sensor using the laser-induced dielectrophoresis is designed and fabricated. The diffusion signal of the first-order diffracted light was detected by using our proposed microfluidic chip.

Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aβ 42 production. Lead compound 3 , with selective Aβ 42 -lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j , which selectively reduced brain Aβ 42 in mice.

Optoelectro-microfluidic sensor based on a laser-induced dielectrophoresis is developed for the biological sensing. A sequential sensing of mass diffusion coefficient is demonstrated using two nanobeads sample.

The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds. It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED50=1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations. Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential.

A MEMS diffusion sensor utilizing the laser-induced dielectrophoresis is developed, and the photoconductive layer is deposited by the plain reactive RF magnetron sputtering method. The nano-scale size difference is observed using the newly fabricated sensor.

In this study, a MEMS sensing device, which is applicable to point-of-care testing (POCT), is developed by integrating an optical manipulation and detection technique. The diffusion coefficient is a parameter, which is sensitive to the size, the construction and the interaction of the sample, thus, the measurement of the diffusion coefficient of the bio-sample, such as proteins, is useful for the clinical diagnosis to detect interactions and conformational changes with high sensitivity. Several diffusion sensing methods have been developed, however, the technique applicable to POCT is not established because of the difficulties due to the requirement of the measurement in a short time and a small sensing device. In this study, in order to realize a high-speed detection (ms ~ s) with small sample volume (~ μl) and small apparatus (tens of cm) without particular preparations, the micro optical diffusion sensor utilizing laser-induced dielectrophoresis (LIDEP), which is a manipulation technique based on optoelectronic tweezers, is developed. The microscale concentration distribution is formed in the microchannel by LIDEP and act as the transient diffraction grating, then, the diffusion phenomenon is optically observed. For these techniques, a photoconductive layer is essential and a hydrogenated amorphous silicon (a-Si:H) deposited by a plasma-enhanced chemical vapor deposition is generally utilized as the layer. In this study, the a-Si:H is deposited using a reactive RF magnetron sputtering method under several conditions, while changing the source gas compositions. The sensing device is fabricated with proposed a-Si:H, and the feasibility study for bio-sample measurement is conducted.

Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation.

Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3-b]pyridine core exhibited potent ACC inhibitory activity and favorable pharmacokinetic profiles in rats.

It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC(50) = 1.9 nM; human 5-HT2c receptor, IC(50) = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC(50) = 0.54 nM), potent in vitro antagonistic activity (IC(50) = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC(50)1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.

The co-crystal structure of the human acetyl-coenzyme A 2 (ACC2) carboxyl transferase domain and the reported compound CP-640186 (1b) suggested that two carbonyl groups are essential for potent ACC2 inhibition. By focusing on enhancing the interactions between the two carbonyl groups and the amino acid residues Gly(2162) and Glu(2230), we used ligand- and structure-based drug design to discover spirolactones bearing a 2-ureidobenzothiophene moiety.

Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4′-fluoro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1′-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity.

An optofluidic diffusion sensor using laser-induced dielectrophoresis in a device with a sputtered a-Si:H layer is presented. Diffusion sensors enabling high-speed measurement have important potential uses as bio-sensors and for quantitative analysis of nano-sized products. The present sensor was developed for measurement in a few seconds by optic observations of the sample diffusion from transient grating formed by laser-induced dielectrophoresis. As a photoconductive layer for the proposed device, we used a sputtered a-Si:H film. The optical (refractive index and extinction coefficient), structural (Raman and IR spectroscopy), and optoelectronic properties of this film, as well as its applicability to the proposed device are characterized. Nano-sized beads were measured by the fabricated device, and its performance as a diffusion sensor was validated.

Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aβ₄₂ production. Lead compound 3, with selective Aβ₄₂-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Aβ₄₂ in mice.

The intestinal absorption of an intact oligopeptide was investigated in rats using a synthetic cationic peptide, 001-C8 (H-MeTyr-Arg-MeArg- d -Leu-NH(CH 2 ) 8 NH 2 ). The peptide was coupled with 4-nitrobenzo-2-oxa-1,3-diazole (NBD) to prepare a fluorescence-labeled derivative 001-C8-NBD (H-MeTyr-Arg-MeArg- d -Leu-NH(CH 2 ) 8 NH-NBD) for the purpose of quantification. The degradation half-life of 001-C8-NBD in jejunal homogenate (1 mg/mL) was 99.5 min, which was significantly longer than that of natural leucine enkephalin (1.14 min). The absorption of 001-C8-NBD was evaluated by the vascular-perfusion method. Intact 001-C8-NBD appeared in the blood time-dependently and the absorption volume at 30 min (2.75 ± 0.14 μL/cm intestine) was significantly larger than that of [ 3 H]PEG 900 (0.88 ± 0.13 μL/cm intestine), of which membrane permeability is very low. The absorption of 001-C8-NBD was greatly reduced by an adsorptive-mediated endocytosis inhibitor, protamine (10 mM). No inhibition of the absorption of [ 3 H]PEG 900 by protamine was observed. The intestinal absorption was also measured by an in vivo loop method. The absorption clearance of 001-C8-NBD measured by this method (0.083 ± 0.008 μL/min/cm intestine) was comparable to that obtained by the vascular perfusion method (0.092 ± 0.005 μL/min/cm intestine). All of these data suggested that 001-C8-NBD was absorbed as the intact oligopeptide in the intestine in vivo. Adsorptive-mediated transcytosis is suggested to have enormous potential as an oral delivery system for peptide and/or protein drugs.

The blood-brain barrier (BBB) is a highly selective membranous barrier regulating the transport of substances in blood into the brain parenchyma. At present, delivery of biologically active peptides or peptide drugs into the brain is quite an important subject from the standpoint of chemotherapy for brain diseases. H–MeTyr–Arg–MeArg–D-Leu–NH(CH2)8NH2 termed 001-C8 was first synthesized to elucidate the structural specificity of peptides for passing through the BBB. The Nα-methylamino acid and D-amino acid residues were appropriately situated in this peptide to protect against the digestion by peptidase. Furthermore, a number of basic peptides were prepared as 001-C8 analogs for studying the relationship between structure and BBB permeability of peptides.

Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.

Melanin-concentrating hormone receptor 1 (MCHR1) antagonists have been studied as potential agents for the treatment of obesity. Initial structure–activity relationship studies of in-house hit compound 1a and subsequent optimization studies resulted in the identification of tetrahydroisoquinoline derivative 23, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-[4-(4-chlorophenyl)piperidin-1-yl]butan-1-one, as a potent hMCHR1 antagonist. A homology model of hMCHR1 suggests that these compounds interact with Asn294 and Asp123 in the binding site of hMCHR1 to enhance binding affinity. Oral administration of compound 23 dose-dependently reduced food intake in diet-induced obesity (DIO)-F344 rats.

The blood-brain barrier (BBB) is a highly selective membranous barrier regulating the transport of substances in blood into the brain parenchyma. At present, delivery of biologically active peptides or peptide drugs into the brain is quite an important subject from the standpoint of chemotherapy for brain diseases. H–MeTyr–Arg–MeArg–D-Leu–NH(CH2)8NH2 termed 001-C8 was first synthesized to elucidate the structural specificity of peptides for passing through the BBB. The Nα-methylamino acid and D-amino acid residues were appropriately situated in this peptide to protect against the digestion by peptidase. Furthermore, a number of basic peptides were prepared as 001-C8 analogs for studying the relationship between structure and BBB permeability of peptides.