-
Eric D Hostetler,
Sandra Sanabria-Bohórquez,
Waisi Eng,
Aniket D Joshi,
Shailendra Patel,
Raymond E Gibson,
Stacey O'Malley,
Stephen M Krause,
Christine Ryan,
Kerry Riffel, [......],
Marleen Depre,
Jan de Hoon,
Inge De Lepeleire,
Tom Reynders,
Jacquelynn J Cook,
H Donald Burns,
Michael Egan,
William Cho,
Koen van Laere,
Richard J Hargreaves
[show abstract]
[hide abstract]
ABSTRACT: Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity (18)F for positron emission tomography (PET) studies. Evaluation of [(18)F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [(18)F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [(18)F]MK-0911 in all grey matter regions. Baseline PET studies with [(18)F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [(18)F]MK-0911 uptake in repeat human baseline PET studies showed a test-retest variability in volume of distribution (V(T)) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [(18)F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [(18)F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [(18)F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states.
NeuroImage 12/2012; · 5.89 Impact Factor
-
Hirohide Nambu,
Miyuki Fukushima,
Hirohiko Hikichi,
Takao Inoue,
Norihiro Nagano,
Yoshio Tahara,
Tadahiro Nambu,
Junko Ito,
Yoshihiro Ogawa, Satoshi Ozaki,
Hisashi Ohta
[show abstract]
[hide abstract]
ABSTRACT: GPR61 is an orphan G protein-coupled receptor whose function remains unknown. The purpose of the present study is to elucidate the importance of GPR61 in metabolism by characterization of GPR61-deficient mice.
Male GPR61-deficient mice were characterized regarding various metabolic parameters, including food intake, body weight, oxygen consumption, body temperature, locomotor activity, and in a pair feeding study. Hypothalamic gene expression was analyzed using real-time quantitative RT-PCR.
GPR61-deficient mice exhibited marked hyperphagia and heavier body weight than wild-type mice. Hyperphagia of GPR61-deficient mice was observed before the differences in body weight became apparent between the genotypes. When body weight difference did become apparent between genotypes, increases in visceral fat pad weight, liver weight, liver triglyceride (TG) content, plasma leptin, and plasma insulin were observed in GPR61-deficient mice, suggesting that GPR61 deficiency caused obesity associated with hyperphagia. Oxygen consumption, body temperature, and locomotor activity were not significantly different between GPR61-deficient and wild-type mice. Pair-fed GPR61-deficient mice had a greater fat mass than wild-type mice despite comparable body weight in both genotypes. The mRNA levels of proopiomelanocortin (POMC) and brain-derived neurotropic factor (BDNF) in the hypothalamus of GPR61-deficient mice were significantly lower than those of wild-type mice.
GPR61-deficient mice exhibited obesity associated with hyperphagia. These findings suggest that GPR61 is involved in the regulation of food intake and body weight, and may be of importance when considering GPR61 as a therapeutic target for obesity or eating disorders.
Life sciences 11/2011; 89(21-22):765-72. · 2.56 Impact Factor
-
Eric D Hostetler,
Waisi Eng,
Aniket D Joshi,
Sandra Sanabria-Bohórquez,
Hiroshi Kawamoto,
Satoru Ito,
Stacey O'Malley,
Stephen Krause,
Christine Ryan,
Shil Patel,
Mangay Williams,
Kerry Riffel,
Gentaroh Suzuki, Satoshi Ozaki,
Hisashi Ohta,
Jacquelynn Cook,
H Donald Burns,
Richard Hargreaves
[show abstract]
[hide abstract]
ABSTRACT: Two moderately lipophilic, high affinity ligands for metabotropic glutamate receptor subtype 1 (mGluR1) were radiolabeled with a positron-emitting radioisotope and evaluated in rhesus monkey as potential PET tracers. Both ligands were radiolabeled with fluorine-18 via nucleophilic displacement of the corresponding 2-chloropyridine precursor with [¹⁸F]potassium fluoride. [¹⁸F]MK-1312 was found to have a suitable signal for quantification of mGluR1 receptors in nonhuman primates and was more thoroughly characterized. In vitro autoradiographic studies with [¹⁸F]MK-1312 in rhesus monkey and human brain tissue slices revealed an uptake distribution consistent with the known distribution of mGluR1, with the highest uptake in the cerebellum, moderate uptake in the hippocampus, thalamus, and cortical regions, and lowest uptake in the caudate and putamen. In vitro saturation binding studies in rhesus monkey and human cerebellum homogenates confirmed that [¹⁸F]MK-1312 binds to a single site with a B(max) /K(d) ratio of 132 and 98, respectively. PET studies in rhesus monkey with [¹⁸F]MK-1312 showed high brain uptake and a regional distribution consistent with in vitro autoradiography results. Blockade of [¹⁸F]MK-1312 uptake with mGluR1 allosteric antagonist MK-5435 dose-dependently reduced tracer uptake in all regions of gray matter to a similarly low level of tracer uptake. This revealed a large specific signal useful for determination of mGluR1 receptor occupancy in rhesus monkey. Taken together, these results are promising for clinical PET studies with [¹⁸F]MK-1312 to determine mGluR1 occupancy of MK-5435.
Synapse 02/2011; 65(2):125-35. · 2.94 Impact Factor
-
Eric D Hostetler,
Sandra Sanabria-Bohórquez,
Hong Fan,
Zhizhen Zeng,
Liza Gantert,
Mangay Williams,
Patricia Miller,
Stacey O'Malley,
Minoru Kameda,
Makoto Ando,
Nagaaki Sato, Satoshi Ozaki,
Shigeru Tokita,
Hisashi Ohta,
David Williams,
Cyrille Sur,
Jacquelynn J Cook,
H Donald Burns,
Richard Hargreaves
[show abstract]
[hide abstract]
ABSTRACT: Neuropeptide Y receptor subtype 1 (NPY Y1) has been implicated in appetite regulation, and antagonists of NPY Y1 are being explored as potential therapeutics for obesity. An NPY Y1 PET tracer is useful for determining the level of target engagement by NPY Y1 antagonists in preclinical and clinical studies. Here we report the synthesis and evaluation of [(18)F]Y1-973, a novel PET tracer for NPY Y1. [(18)F]Y1-973 was radiolabeled by reaction of a primary chloride with [(18)F]KF/K2.2.2 followed by deprotection with HCl. [(18)F]Y1-973 was produced with high radiochemical purity (>98%) and high specific activity (>1000 Ci/mmol). PET studies in rhesus monkey brain showed that the distribution of [(18)F]Y1-973 was consistent with the known NPY Y1 distribution; uptake was highest in the striatum and cortical regions and lowest in the pons, cerebellum nuclei, and brain stem. Blockade of [(18)F]Y1-973 uptake with NPY Y1 antagonist Y1-718 revealed a specific signal that was dose-dependently reduced in all regions of grey matter to a similarly low level of tracer uptake, indicative of an NPY Y1 specific signal. In vitro autoradiographic studies with [(18)F]Y1-973 in rhesus monkey and human brain tissue slices revealed an uptake distribution consistent with the in vivo PET studies. Highest binding density was observed in the dentate gyrus, caudate-putamen, and cortical regions; moderate binding density in the hypothalamus and thalamus; and lowest binding density in the globus pallidus and cerebellum. In vitro saturation binding studies in rhesus monkey and human caudate-putamen homogenates confirmed a similarly high B(max)/K(d) ratio for [(18)F]Y1-973, suggesting the tracer may provide a specific signal in human brain of similar magnitude to that observed in rhesus monkey. [(18)F]Y1-973 is a suitable PET tracer for imaging NPY Y1 in rhesus monkey with potential for translation to human PET studies.
NeuroImage 11/2010; 54(4):2635-42. · 5.89 Impact Factor
-
Eric D. Hostetler,
Waisi Eng,
Aniket D. Joshi,
Sandra Sanabria-Bohórquez,
Hiroshi Kawamoto,
Satoru Ito,
Stacey O'Malley,
Stephen Krause,
Christine Ryan,
Shil Patel,
Mangay Williams,
Kerry Riffel,
Gentaroh Suzuki, Satoshi Ozaki,
Hisashi Ohta,
Jacquelynn Cook,
H. Donald Burns,
Richard Hargreaves
[show abstract]
[hide abstract]
ABSTRACT: Two moderately lipophilic, high affinity ligands for metabotropic glutamate receptor subtype 1 (mGluR1) were radiolabeled with a positron-emitting radioisotope and evaluated in rhesus monkey as potential PET tracers. Both ligands were radiolabeled with fluorine-18 via nucleophilic displacement of the corresponding 2-chloropyridine precursor with [18F]potassium fluoride. [18F]MK-1312 was found to have a suitable signal for quantification of mGluR1 receptors in nonhuman primates and was more thoroughly characterized. In vitro autoradiographic studies with [18F]MK-1312 in rhesus monkey and human brain tissue slices revealed an uptake distribution consistent with the known distribution of mGluR1, with the highest uptake in the cerebellum, moderate uptake in the hippocampus, thalamus, and cortical regions, and lowest uptake in the caudate and putamen. In vitro saturation binding studies in rhesus monkey and human cerebellum homogenates confirmed that [18F]MK-1312 binds to a single site with a Bmax/Kd ratio of 132 and 98, respectively. PET studies in rhesus monkey with [18F]MK-1312 showed high brain uptake and a regional distribution consistent with in vitro autoradiography results. Blockade of [18F]MK-1312 uptake with mGluR1 allosteric antagonist MK-5435 dose-dependently reduced tracer uptake in all regions of gray matter to a similarly low level of tracer uptake. This revealed a large specific signal useful for determination of mGluR1 receptor occupancy in rhesus monkey. Taken together, these results are promising for clinical PET studies with [18F]MK-1312 to determine mGluR1 occupancy of MK-5435. Synapse 2011. © 2010 Wiley-Liss, Inc.
Synapse 06/2010; 65(2):125 - 135. · 2.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Periodic and spontaneous Ca(2+) spikes are observed in neurons during development of the central nervous system, and spontaneous changes in intracellular Ca(2+) concentration in neurons play important roles in the development of neural circuits. To clarify the roles of metabotropic glutamate receptors (mGluRs) in the regulation of spontaneous Ca(2+) spikes, we investigated the effects of selective and nonselective mGluRs ligands on primary cultures of rat cortical neurons. Cultured cortical neurons expressed all eight mGluR subtypes on reverse transcription-PCR. The mGluR2 and mGluR3 agonists LY379268, LY354740, and (2R,4R)-APDC increased the amplitude but decreased the frequency of spontaneous Ca(2+) spikes in cultured cortical neurons. The effects of these mGluR2 and mGluR3 agonists were completely inhibited by the presence of a potent mGluR2 and mGluR3 antagonist, LY341495, and by pretreatment with pertussis toxin. No significant effect was observed with either activation or inhibition of mGluR1, mGluR4, mGluR5, mGluR6, mGluR7, and mGluR8 on the spontaneous Ca(2+) spikes in cultured cortical neurons. These findings indicate that, among mGluRs, the group II mGluR subtypes mGluR2 and mGluR3 play principal roles in modulation of spontaneous Ca(2+) spikes.
Journal of Neuroscience Research 03/2010; 88(10):2252-62. · 2.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett.2009, 19, 3627; Kobayashi et al., Bioorg. Med. Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group demonstrated that examining the structure-activity relationship for novel templates allowed the identification of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole. These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or reduced hERG affinity.
Bioorganic & medicinal chemistry letters 09/2009; 19(16):4611-6. · 2.65 Impact Factor
-
Minoru Kameda,
Makoto Ando,
Chisato Nakama,
Kensuke Kobayashi,
Hiroshi Kawamoto,
Sayaka Ito,
Tomoki Suzuki,
Takeshi Tani, Satoshi Ozaki,
Shigeru Tokita,
Nagaaki Sato
[show abstract]
[hide abstract]
ABSTRACT: A series of 2,4-diaminopyridine derivatives was synthesized and evaluated as potential candidates for neuropeptide Y (NPY) Y1 receptor positron emission tomography (PET) tracers. Derivatives bearing substitutions allowing reliable access to radiolabeling were designed, focusing on Y1 binding affinity and lipophilicity. The advanced derivatives 2n and 2o were identified as promising PET tracer candidates.
Bioorganic & medicinal chemistry letters 08/2009; 19(17):5124-7. · 2.65 Impact Factor
-
Gentaroh Suzuki,
Hiroko Kawagoe-Takaki,
Takao Inoue,
Toshifumi Kimura,
Hirohiko Hikichi,
Takashi Murai,
Akio Satow,
Mikiko Hata,
Shunsuke Maehara,
Satoru Ito,
Hiroshi Kawamoto, Satoshi Ozaki,
Hisashi Ohta
[show abstract]
[hide abstract]
ABSTRACT: The aim of this study was to clarify the relationship between receptor occupancy and in vivo pharmacological activity of mGluR1 antagonists. The tritiated mGluR1-selective allosteric antagonist [(3)H]FTIDC (4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide) was identified as a radioligand having high affinity for mGluR1-expressing CHO cells (K(D) = 2.1 nM) and mouse cerebellum (K(D) = 3.7 nM). [(3)H]FTIDC bound to mGluR1 was displaced by structurally unrelated allosteric antagonists, suggesting there is a mutual binding pocket shared with different allosteric antagonists. The binding specificity of [(3)H]FTIDC for mGluR1 in brain sections was demonstrated by the lack of significant binding to brain sections prepared from mGluR1-knockout mice. Ex vivo receptor occupancy with [(3)H]FTIDC revealed that the receptor occupancy level by FTIDC correlated well with FTIDC dosage and plasma concentration. Intracerebroventricular administration of (S)-3,5-dihydroxyphenylglycine is known to elicit face washing behavior that is mainly mediated by mGluR1. Inhibition of this behavioral change by FTIDC correlated with the receptor occupancy level of mGluR1 in the brain. A linear relationship between the receptor occupancy and in vivo activity was also demonstrated using structurally diverse mGluR1 antagonists. The receptor occupancy assays could help provide guidelines for selecting appropriate doses of allosteric mGluR1 antagonist for examining the function of mGluR1 in vivo.
Journal of Pharmacological Sciences 07/2009; 110(3):315-25. · 2.08 Impact Factor
-
Atsushi Satoh,
Takeshi Sagara,
Hiroki Sakoh,
Masaya Hashimoto,
Hiroshi Nakashima,
Tetsuya Kato,
Yasuhiro Goto,
Sayaka Mizutani,
Tomoko Azuma-Kanoh,
Takeshi Tani,
Shoki Okuda,
Osamu Okamoto, Satoshi Ozaki,
Yoshikazu Iwasawa,
Hisashi Ohta,
Hiroshi Kawamoto
[show abstract]
[hide abstract]
ABSTRACT: Our efforts to optimize prototype opioid receptor-like 1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine 10. 10 showed potent ORL1 antagonistic activity, excellent selectivity over other opioid receptors, and in vivo efficacy after oral dosing. Currently clinical trials of 10 are underway.
Journal of Medicinal Chemistry 07/2009; 52(14):4091-4. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Currently tested allosteric modulators for metabotropic glutamate receptor 1 (mGluR1) are known to regulate the activity of mGluR1 mainly through transmembrane (TM) domain 6 and/or 7. We identified a novel interaction site, N760 in TM5, which negatively regulates activation of mGluR1 with a newly discovered selective mGluR1 antagonist, 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one (CFMMC). CFMMC inhibited L-glutamate-induced intracellular Ca(2+) mobilization ([Ca(2+)]i) in Chinese hamster ovary (CHO) cells expressing recombinant human mGluR1a with IC(50) value of 50 nM, whereas it did not inhibit [Ca(2+)]i in CHO cells expressing human mGluR5a (IC(50); >10 microM). To identify the amino acid residues critical for antagonism of CFMMC, we constructed various point mutants of human mGluR1 and evaluated them in [Ca(2+)]i assays. The inhibitory effects of CFMMC were significantly affected in point mutations of either I725 in TM4 or N760 in TM5, as well as mutations of W798, F801 and Y805 in TM6 or T815 in TM7. Further studies revealed that antagonistic activities of not only CFMMC but also other, structurally unrelated, mGluR1 antagonists such as 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198) and Compound 1 were reduced in N760 mutated mGluR1a. These results indicate that some mGluR1 allosteric antagonists require N760 in TM5 to demonstrate negative modulation of mGluR1 in addition to the reported amino acid residues in TM6 and TM7.
Neuropharmacology 07/2009; 57(4):438-45. · 4.81 Impact Factor
-
Kensuke Kobayashi,
Tomohiro Tsujita,
Hirokatsu Ito, Satoshi Ozaki,
Takeshi Tani,
Yasuyuki Ishii,
Shoki Okuda,
Kiyoshi Tadano,
Takahiro Fukuroda,
Hisashi Ohta,
Osamu Okamoto
[show abstract]
[hide abstract]
ABSTRACT: Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.
Bioorganic & medicinal chemistry letters 07/2009; 19(16):4729-32. · 2.65 Impact Factor
-
Kensuke Kobayashi,
Minaho Uchiyama,
Hirokatsu Ito,
Hirobumi Takahashi,
Takashi Yoshizumi,
Hiroki Sakoh,
Yasushi Nagatomi,
Masanori Asai,
Hiroshi Miyazoe,
Tomohiro Tsujita,
Mioko Hirayama, Satoshi Ozaki,
Takeshi Tani,
Yasuyuki Ishii,
Hisashi Ohta,
Osamu Okamoto
[show abstract]
[hide abstract]
ABSTRACT: The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.
Bioorganic & medicinal chemistry letters 06/2009; 19(13):3627-31. · 2.65 Impact Factor
-
Kensuke Kobayashi,
Tetsuya Kato,
Izumi Yamamoto,
Atsushi Shimizu,
Sayaka Mizutani,
Masanori Asai,
Hiroshi Kawamoto,
Satoru Ito,
Takashi Yoshizumi,
Mioko Hirayama, Satoshi Ozaki,
Hisashi Ohta,
Osamu Okamoto
[show abstract]
[hide abstract]
ABSTRACT: A structure-activity relationship (SAR) study on the benzimidazole series of opioid receptor-like 1 (ORL1) antagonists related to 1 is described. Optimization of 1 by introduction of a hydrophilic substituent into the thioether part resulted in identification of potent ORL1 antagonists with high selectivity over binding affinity for hERG and other opioid receptors.
Bioorganic & medicinal chemistry letters 05/2009; 19(11):3100-3. · 2.65 Impact Factor
-
Kensuke Kobayashi,
Minaho Uchiyama,
Hirobumi Takahashi,
Hiroshi Kawamoto,
Satoru Ito,
Takashi Yoshizumi,
Hiroshi Nakashima,
Tetsuya Kato,
Atsushi Shimizu,
Izumi Yamamoto, [......],
Mioko Hirayama, Satoshi Ozaki,
Takeshi Tani,
Yasuyuki Ishii,
Takeshi Tanaka,
Takanobu Mochidome,
Kiyoshi Tadano,
Takahiro Fukuroda,
Hisashi Ohta,
Osamu Okamoto
[show abstract]
[hide abstract]
ABSTRACT: The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.
Bioorganic & medicinal chemistry letters 05/2009; 19(11):3096-9. · 2.65 Impact Factor
-
Akio Satow,
Gentaroh Suzuki,
Shunsuke Maehara,
Hirohiko Hikichi,
Takeshi Murai,
Takashi Murai,
Hiroko Kawagoe-Takaki,
Mikiko Hata,
Satoru Ito, Satoshi Ozaki,
Hiroshi Kawamoto,
Hisashi Ohta
[show abstract]
[hide abstract]
ABSTRACT: A newly discovered metabotropic glutamate receptor (mGluR) 1 allosteric antagonist, 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one (CFMTI), was tested both in vitro and in vivo for its pharmacological effects. CFMTI demonstrated potent and selective antagonistic activity on mGluR1 in vitro and in vivo after oral administration. CFMTI inhibited L-glutamate-induced intracellular Ca(2+) mobilization in Chinese hamster ovary cells expressing human and rat mGluR1a, with IC(50) values of 2.6 and 2.3 nM, respectively. The selectivity of CFMTI to mGluR1 over mGluR5 was >2000-fold, and CFMTI at 10 microM showed no agonistic or antagonistic activities toward other mGluR subtypes and other receptors. It antagonized face-washing behavior in mice induced by (S)-3,5-dihidroxyphenylglycine at a dose range of 3 to 30 mg/kg, for which receptor occupancy was 73 to 94%. As with the classical neuroleptic haloperidol and an atypical antipsychotic, clozapine, orally administered CFMTI reduced methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition (PPI) at the same dose range as required to antagonize the face-washing behavior. CFMTI and clozapine improved ketamine-induced hyperlocomotion, PPI disruption and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-induced social withdrawal without any cataleptogenic activities, whereas haloperidol only improved ketamine-induced hyperlocomotion. CFMTI, unlike clozapine, caused neither hypolocomotion nor motor incoordination at therapeutic doses. In c-fos expression studies, CFMTI and clozapine increased the number of fos-positive neurons in the nucleus accumbens and medial prefrontal cortex but not in the dorsolateral striatum. These results suggest that the antipsychotic activities of mGluR1 antagonists are more similar to those of atypical antipsychotics than those of typical antipsychotics.
Journal of Pharmacology and Experimental Therapeutics 05/2009; 330(1):179-90. · 3.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We succeeded in cloning the rhesus monkey nociceptin/orphanin FQ peptide (NOP) receptor. The nucleotide sequence and amino acid sequence of the rhesus monkey NOP receptor were 95.9% and 97.8%, respectively, identical to the human NOP receptor. There was no significant difference between the rhesus monkey NOP receptor and the human NOP receptor in the binding affinity of [(125)I] [Thy(14)]nociceptin and the binding of [(35)S]guanosine 5'-O-(gamma thio)triphospate ([(35)S]GTPgammaS) stimulated by nociceptin/orphanin FQ (N/OFQ). A selective NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one ((+)-J-113397) inhibited the [(35)S]GTPgammaS binding activated by N/OFQ using the membrane of the rhesus monkey NOP receptor. The antagonistic activity of (+)-J-113397 to the rhesus monkey NOP receptor was comparable to that to the human NOP receptor. Thus, N/OFQ acts via activation of the NOP receptor in both human and rhesus monkeys without significant species differences.
Genes & Genetic Systems 01/2009; 84(5):319-25. · 0.95 Impact Factor
-
Takashi Yoshizumi,
Hirobumi Takahashi,
Hiroshi Miyazoe,
Yuichi Sugimoto,
Tomohiro Tsujita,
Tetsuya Kato,
Hirokatsu Ito,
Hiroshi Kawamoto,
Mioko Hirayama,
Daisuke Ichikawa, [......], Satoshi Ozaki,
Yoshihiro Shibata,
Takeshi Tani,
Masato Chiba,
Yasuyuki Ishii,
Shoki Okuda,
Kiyoshi Tadano,
Takahiro Fukuroda,
Osamu Okamoto,
Hisashi Ohta
[show abstract]
[hide abstract]
ABSTRACT: A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.
Journal of Medicinal Chemistry 08/2008; 51(13):4021-9. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1'-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4'-piperidine], which exhibits excellent selectivity to mu, kappa, and human ether-a-go-go related gene potassium channel.
Bioorganic & medicinal chemistry letters 08/2008; 18(13):3778-82. · 2.65 Impact Factor
-
Osamu Okamoto,
Kensuke Kobayashi,
Hiroshi Kawamoto,
Satoru Ito,
Atsushi Satoh,
Tetsuya Kato,
Izumi Yamamoto,
Sayaka Mizutani,
Masaya Hashimoto,
Atsushi Shimizu,
Hiroki Sakoh,
Yasushi Nagatomi,
Yoshikazu Iwasawa,
Hiroyuki Takahashi,
Yasuyuki Ishii, Satoshi Ozaki,
Hisashi Ohta
[show abstract]
[hide abstract]
ABSTRACT: Structure-activity studies on benzimidazole lead 1 obtained from library screening led to the discovery of potent and selective ORL1 antagonist 28, 5-chloro-2-[(1-ethyl-1-methylpropyl)thio]-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-benzimidazole, which is structurally distinct from conventional non-peptide antagonists known to date.
Bioorganic & medicinal chemistry letters 07/2008; 18(11):3278-81. · 2.65 Impact Factor
