Biomedical subjects

Shigeyuki Chaki

Publications and source records attributed to Shigeyuki Chaki.

At least 37 records · Page 2Linked to original sources

PubMed2005

Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists.

Melanin-concentrating hormone (MCH) is a cyclic peptide produced in the lateral hypothalamus. It has been implicated in a number of physiological processes including feeding behavior, energy balance, and the regulation of emotional states. Here, we report in vitro and in vivo profiles of ATC0065 [N(2)-[cis-4-({2-[4-bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-N(4), N(4)-dimethylquinazoline-2,4-diamine dihydrochloride] and ATC0175 [N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride], newly synthesized MCH receptor 1 (MCHR1) antagonists. Both ATC0065 and ATC0175 had high affinities for human MCHR1 with IC(50) values of 15.7 +/- 1.95 and 7.23 +/- 0.59 nM, respectively. Both ATC0065 (IC(50) = 21.4 +/- 1.57 nM) and ATC0175 (IC(50) = 13.5 +/- 0.78 nM) showed potent antagonist activities at MCHR1, as assessed by MCH-increased guanosine 5'-O-(3-[(35)S]thio)phosphate ([(35)S]GTPgammaS) binding to human MCHR1. Oral administration of ATC0065 (3-30 mg/kg) or ATC0175 (1-10 mg/kg) significantly reduced immobility time in the forced swimming test in rats, indicating antidepressant-like effects. Both ATC0065 and ATC0175 significantly reversed swim stress-induced anxiety in the elevated plus-maze test in rats and stress-induced hyperthermia in mice. ATC0175 significantly increased social interaction between unfamiliar rats and reduced separation-induced vocalizations in guinea pig pups, indicating anxiolytic potential. In contrast, ATC0065 and ATC0175 did not affect spontaneous locomotor activity or rotarod performance in rats. These findings indicate that ATC0065 and ATC0175 are potent and orally active MCHR1 antagonists with anxiolytic and antidepressant activity in rodents.

Administration, Oral↗

PubMed2005

Anxiolytic-like effect of a selective and non-peptidergic melanocortin 4 receptor antagonist, MCL0129, in a social interaction test.

The social interaction test is an animal behavioral test of anxiety. Brain melanocortins such as alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH) have anxiogenic effects in this test. Melanocortins have five receptor subtypes (MC1-MC5). Among them, MC3 and MC4 receptor are mainly expressed in the brain. We investigated the involvement of MC4 receptor in a social interaction test, using Ac-[Nle(4),Asp(5),D-Phe(7),Lys(10)]alpha-MSH-(4-10)-NH2 (MT II), an MC4 receptor agonist, and 1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129), a selective and nonpeptide MC4 receptor antagonist. MT II dose-dependently and significantly reduced the time spent in social interaction. Acute administration of MCL0129 had no effect on the results of this test. In contrast, when given repeatedly for 1 week, MCL0129 significantly and dose-dependently increased the time spent in social interaction without affecting locomotor activity. These results suggest that MC4 receptor is involved in social interaction, and that MCL0129, an MC4 receptor antagonist, has an anxiolytic-like effect in this model.

Animals↗

PubMed2005

Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors.

Glutamatergic abnormalities play roles in several psychiatric disorders. Glutamate acts at two classes of receptors, ionotropic and metabotropic glutamate receptors (mGluR), the latter is classified into three group, based on receptor homology and signaling mechanisms. Among them, recent pharmacological and histochemical studies suggest that the group II mGluR (mGluR2 and mGluR3) plays crucial roles in the control of emotional states. We previously reported that MGS0039, a selective group II mGluR antagonist, exhibited dose-dependent antidepressant-like effects in some animal models. However, the mechanism by which group II mGluR antagonists exhibit such effects is still unclear. In the present two studies, we examined neuropharmacological effects of group II mGluR antagonists on monoaminergic neurons. In an electrophysiological study, MGS0039 dose-dependently and significantly increased the firing rate of dorsal raphe nucleus (DRN) serotonergic neurons. LY341495, another group II mGluR antagonist, also increased DRN serotonergic neural activity significantly. Consistent with the findings of this electrophysiological study, MGS0039 significantly increased extracellular level of serotonin in rat medial prefrontal cortex in a microdialysis study. In contrast, MGS0039 had no effect on the activity of locus coeruleus noradrenergic neurons. These findings suggest that modulation of serotonergic neuron might be, at least in part, responsible for the antidepressant-like effects of group II mGluR antagonists.

Action Potentials↗

PubMed2005

Involvement of melanocortin-4 receptor in anxiety and depression.

The melanocortins, which are derived from proopiomelanocortin, have a variety of physiological functions mediated membrane surface receptors. To date, five subtypes have been cloned. With the cloning of melanocortin receptors, studies with genetic models, and development of selective compounds, the physiological roles of the five melanocortin receptors have begun to be understood. The melanocortin-4 receptor (MC4R), which is predominantly expressed in the central nervous system, has in particular become the focus of much attention in recent years because of the critical roles it plays in a wide range of functions, including feeding, sexual behavior, and stress. Recent development of selective antagonists for the MC4R has provided pharmacological evidence that blockade of MC4R could be a useful way of alleviating numerous conditions such as anxiety/depression, pain, and addiction to drugs of abuse.

Animals↗

PubMed2005

ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety.

Melanin-concentrating hormone (MCH) has been implicated in a variety of physiological events. Recent studies clearly suggest that MCH plays an important role in the regulation of stress and emotion. To date, two receptor subtypes of MCH (MCH1R and MCH2R) have been identified. MCH1R has been suggested to mediate most of the physiological functions of MCH. Recently, we synthesized an orally active, nonpeptidic antagonist of MCH1R, N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride (ATC0175). This compound is a potent antagonist with a high affinity for MCH1R and additional affinities for 5-HT1A and 5-HT2B receptors. The receptor binding and the functional assay (MCH-induced increase in [Ca2+]i) indicated that ATC0175 is a noncompetitive antagonist at MCH1Rs. ATC0175 exhibited anxiolytic effects in numerous animal models of anxiety including the elevated plus-maze test, social interaction test, stress-induced hyperthermia and maternal separation-induced vocalization. Like with other stress-related peptide receptor antagonists, such as antagonists of corticotropin-releasing factor or vasopressin V1b receptor antagonists, anxiolytic effects of ATC0175 were more pronounced in models containing a stress component. ATC0175 also exhibited antidepressant effects in the forced swimming test. ATC0175 increased swimming performance without altering climbing behavior, as observed with selective serotonin reuptake inhibitors. ATC0175 has adequate ADME profile (reasonable oral bioavailability and brain penetration) and potent oral activity in animal models. In contrast, ATC0175 did not affect spontaneous locomotor activity, hexobarbital-induced sleeping time and did not impair rotarod performance. Thus, ATC0175 may be devoid of unwanted central nervous system side effects, which are sometimes observed with current medications. In addition, ATC0175 was well tolerated in rat repeated toxicity study, and had no genotoxic liability. Therefore, ATC0175 has the potential to be effective in the treatment of patients with depression and/or anxiety disorders.

Animals↗

PubMed2004

Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test.

Glutamatergic abnormalities are involved in several psychiatric disorders. Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder. MGS0039, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, is a novel group II metabotropic glutamate (mGlu) receptor antagonist. We examined MGS0039's potential anti-obsessive-compulsive disorder activity, using the marble-burying behavior test as a model of obsessive-compulsive disorder. MGS0039 as well as LY341495 ((2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycycloprolyl)glycine), another group II mGlu receptor antagonist, inhibited marble-burying behavior. We also demonstrated that this effect was significantly attenuated by a group II mGlu receptor agonist. This data indicates that group II mGlu receptor antagonists may exert anti-obsessive-compulsive disorder effects in clinical use.

Animals↗

PubMed2004

Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists.

Novel group II metabotropic glutamate receptor (mGluR) antagonists, 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, were discovered by the incorporation of a hydroxy or alkoxyl group onto the C-3 portion of selective and potent group II mGluR agonist 5, (1R,2S,5R,6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Among these compounds, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (-)-11be (MGS0039) was a highly selective and potent group II mGluR antagonist with the best pharmacokinetic profile. Compound (-)-11be exhibited high affinities for mGlu 2 (Ki = 2.38 +/- 0.40 nM) and mGlu 3 (4.46 +/- 0.31 nM) but low affinity for mGluR 7 (Ki = 664 +/- 106 nM), and potent antagonist activities for mGlu 2 (IC50 = 20.0 +/- 3.67 nM) and mGluR 3 (IC50 = 24.0 +/- 3.54 nM) but much less potent antagonist activities for mGlu 4 (IC50 = 1740 +/- 1080 nM), mGlu 6 (IC50 = 2060 +/- 1270 nM), mGlu 1 (IC50 = 93300 +/- 14600 nM), and mGluR 5 (IC(50) = 117000 +/- 38600 nM). No significant agonist activities of (-)-11be were found for mGluRs 2, 3, 4, 6, 1, and 5 (EC50 > 100,000 nM). Furthermore, (-)-11be exhibited dose-dependent oral absorption (plasma C(max): 214 +/- 56.7, 932 +/- 235, and 2960 +/- 1150 ng/mL for 3 mg/kg, 10 mg/kg, and 30 mg/kg, po, respectively) and acceptable blood-brain barrier penetration (brain C(max): 13.2 ng/mL for 10 mg/kg, p.o. 6 h). In this paper, we report the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, and pharmacokinetic profiles of several typical compounds.

Administration, Oral↗

PubMed2004

Design, synthesis, and structure-activity relationships of novel tetracyclic compounds as peripheral benzodiazepine receptor ligands.

The peripheral benzodiazepine receptor (PBR) is pharmacologically distinct from the central benzodiazepine receptor (CBR) and has been identified in a wide range of peripheral tissues as well as in the central nervous system. Although numerous studies have been performed of it, the physiological roles and functions of the PBR are still unclear. In the present study, in exploring new types of ligands for PBR, we found that a new series of compounds having a tetracyclic ring system, which were designed from FGIN-1-27, exhibited high affinities for PBR. We prepared and evaluated them for PBR affinities. The results of binding tests showed that 12e and 12f were the most potent PBR ligands among them (12e: IC(50)=0.44nM, 12f: IC(50)=0.37nM). In this paper, we present the design, synthesis, and structure-activity relationships (SARs) of novel tetracyclic compounds.

Cyclization↗

PubMed2004

Increased cell proliferation in the adult mouse hippocampus following chronic administration of group II metabotropic glutamate receptor antagonist, MGS0039.

We have previously reported that MGS0039, a novel antagonist of group II metabotropic glutamate receptors (mGluRs), exerts antidepressant-like effects in experimental animal models. Recent studies suggest that the behavioral effects of chronic antidepressant treatment are mediated by the stimulation of neurogenesis in the hippocampus. In the present study, we examined the effects of MGS0039 on cell proliferation in the adult mouse hippocampus. MGS0039 (5 or 10mg/kg) or fluvoxamine was administered chronically to male ICR mice over a period of 14 days. Multiple bromodeoxyuridine (BrdU) administrations were performed after the last drug injection to label dividing cells. Immunohistochemical analyses after BrdU injections revealed that chronic MGS0039 treatment enhanced BrdU-positive cells in the dentate gyrus ( approximately 62% increase) in the same manner as chronic fluvoxamine treatment. This is the first in vivo study to demonstrate an increase in cell proliferation following a blockade of group II mGluRs. These findings raise the possibility that MGS0039 may exert antidepressant-like effects by modulating cell proliferation in the hippocampus.

Animals↗

PubMed2004

Monkey corticotropin-releasing factor1 receptor: Complementary DNA cloning and pharmacological characterization.

The full-length complementary DNA (cDNA) of monkey corticotropin-releasing factor type 1 (CRF1) receptor was isolated from a rhesus monkey (Macaca mulatta) amygdala cDNA library. The cloned monkey CRF1 receptor cDNA has 2,374 bp with an open reading frame encoding a 415-amino acid protein. The sequence of the monkey CRF1 receptor cDNA showed a high degree of sequence identity with other species of CRF1 receptors, and being 99.5% identical to human CRF1 receptors. When monkey CRF1 was expressed into COS-7 cells, high specific binding of [125I]-ovine CRF was observed. CRF and CRF-related peptides inhibited [125I]-ovine CRF binding in a concentration-dependent manner. IC50 values of ovine CRF, human/rat CRF, sauvagine and urotensin I were 23.5 +/- 7.4, 22.7 +/- 10.8, 27.5 +/- 12.3 and 14.2 +/- 7.0 nM, respectively. CRF1 receptor specific antagonists, such as CP-154,526, SC241 and CRA1000, also inhibited the [125I]-ovine CRF binding, with IC50 values of 3.9 +/- 0.4, 43.5 +/- 8.0 and 19.8 +/- 2.0 nM, respectively. GTP and its nonhydrolyzed analogue, GTPgammaS, reduced [125I]-ovine CRF binding, while ATP had a negligible effect, thereby indicating that the monkey CRF1 receptor belongs to a family of G-protein coupled receptors. CRF and its related peptides increased cyclic AMP formation concentration-dependently in COS-7 cells transiently expressing the monkey CRF1 receptor. Monkey CRF1 was expressed abundantly in the pituitary, cerebral cortex, hippocampus, amygdala and cerebellum. Thus the monkey CRF1 receptor and the human CRF1 receptor have similar molecular and pharmacological characteristics.

Amino Acid Sequence↗

PubMed2004

Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450.

1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate (R278995/CRA0450) is a newly synthesized corticotropin-releasing factor subtype 1 (CRF(1)) receptor antagonist. In the present study, in vitro and in vivo pharmacological profiles of R278995/CRA0450 were investigated. R278995/CRA0450 showed high affinity for recombinant and native CRF(1) receptors without having affinity for the CRF(2) receptor. R278995/CRA0450 attenuated CRF-induced cyclic AMP formation in AtT-20 cells and CRF-induced forepaw treading in gerbils, indicating that R278995/CRA0450 is an antagonist of the CRF(1) receptor. In addition to CRF(1) receptor antagonism, R278995/CRA0450 showed high affinity for the sigma(1) receptor, and attenuated (+)-SKF10,047-induced head-weaving behavior, suggesting sigma(1) receptor antagonism. R278995/CRA0450 showed dose-dependent in vivo occupancy when assessed by ex vivo receptor binding, indicating good brain penetration. R278995/CRA0450 did not alter spontaneous anxiety when tested in the rat elevated plus maze (up to 3 mg/kg, p.o.) or lick suppression test (up to 10 mg/kg, i.p.). However, potent anxiolytic-like properties were observed in rats subjected to swim stress prior to testing on the elevated plus-maze, indicating activity primarily in tests taxing stress-induced anxiety. R278995/CRA0450 was inactive in mouse tail suspension, rat forced swim and rat differential-reinforcement-of-low-rate 72-s (DRL72), while it showed dose-dependent antidepressant-like effects in the rat learned helplessness paradigm and the olfactory bulbectomy model, demonstrating activity in a subset of animal models of depression associated with subchronic stress exposure. No or only mild effects were seen in tests of locomotor activity, motor coordination and sedation. These results indicate that R278995/CRA0450 is an orally active CRF(1) and sigma(1) receptor antagonist with potent anxiolytic-like and antidepressant-like activities.

Animals↗

PubMed2004

Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands.

Since the peripheral benzodiazepine receptor (PBR) has been primarily found as a high-affinity binding site for diazepam in rat kidney, numerous studies of it have been performed. However, the physiological role and functions of PBR have not been fully elucidated. Currently, we presented the pharmacological profile of two high and selective PBR ligands, N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl)acetamide (7-096, DAA1106) (PBR: IC(50)=0.28 nM) and N-(4-chloro-2-phenoxyphenyl)-N-(2-isopropoxybenzyl)acetamide (7-099, DAA1097) (PBR: IC(50)=0.92 nM). The compounds are aryloxyanilide derivatives, and identified with known PBR ligands such as benzodiazepine (1, Ro5-4864), isoquinoline (2, PK11195), imidazopyridine (3, Alpidem), and indole (5, FGIN-1-27) derivatives. The aryloxyanilide derivatives, which have been derived by opening the diazepine ring of 1, are a novel class as PBR ligands and have exhibited high and selective affinity for peripheral benzodiazepine receptors (PBRs). These novel derivatives would be useful for exploring the functions of PBR. In this paper, the design, synthesis and structure-affinity relationships of aryloxyanilide derivatives are described.

Acetamides↗

PubMed2004

MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity.

The present study describes the pharmacological profile of (1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a novel group II mGluR antagonist. MGS0039 showed high affinity for both mGluR2 (Ki = 2.2 nM) and mGluR3 (Ki = 4.5 nM), which are comparable to LY341495, another group II mGluR antagonist. MGS0039 attenuated both glutamate-induced inhibition of forskolin-evoked cyclic AMP formation in CHO cells expressing mGluR2 (IC50 = 20 nM) or mGluR3 (IC50 = 24 nM) and glutamate-increased [35S]GTPgammaS binding to mGluR2 (pA2 = 8.2), which means that MGS0039 acts as an antagonist. MGS0039 shifted the dose-response curve of glutamate-increased [35S]GTPgammaS binding rightward without altering the maximal response, and thereby indicating competitive antagonism. MGS0039 showed no significant effects on other mGluRs as well as the other receptors and transporters we studied. MGS0039 (0.3-3 mg/kg, i.p.) as well as LY341495 (0.1-3 mg/kg, i.p.) had dose-dependent antidepressant-like effects in the rat forced swim test and in the mouse tail suspension test. In contrast, MGS0039 (0.3-3 mg/kg, i.p.) had no apparent effect in the rat social interaction test and in the rat elevated plus-maze. These results indicate that MGS0039 is a potent and selective antagonist of group II mGluR, and that group II mGluR antagonists, like MGS0039, have an antidepressant-like potential in experimental animal models.

Animals↗

PubMed2004

The role of the DRY motif of human MC4R for receptor activation.

We constructed several mutant human MC4R cDNAs by site directed mutagenesis and expressed these receptors in COS-1 cells. The conserved DRY motif among GPCRs was mutated to generate eight mutants. While no MC4R ligand binding was detected in any of the mutants, one mutant, D146A, resulted in higher cAMP production in cells than the wild-type receptor without ligand stimulation.

Amino Acid Motifs↗

PubMed2004

Regulation of CRF, POMC and MC4R gene expression after electrical foot shock stress in the rat amygdala and hypothalamus.

We investigated the effects of electrical foot shock stress on the melanocortin signaling cascade and the hypothalamus-pituitary-adrenal (HPA) system by observing levels of mRNA expression of corticotropin releasing factor (CRF), pro-opiomelanocortin (POMC), and melanocortin receptor subtype 4 (MC4R) in the rat amygdala and hypothalamus. When rats were exposed to electrical shock for 0.5 hr or 1 hr, plasma ACTH and corticosterone concentrations increased, indicating stress. The rats were then sacrificed to obtain RNA preparations from the brain tissue. In the amygdala, the expression of MC4R and POMC mRNA as well as CRF mRNA was significantly increased by electrical foot shock stress. In the hypothalamus, MC4R and POMC mRNA increased, but CRF mRNA remained unchanged. The duration of increased gene expression of MC4R and POMC in the amygdala was more sustained than in the hypothalamus. These results have provided the first evidence that exposure to stress increases expression of the MC4R system in the amygdala and hypothalamus.

Amygdala↗

PubMed2003

Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in rats.

The melanocortin-4 (MC4) receptor may possibly be involved in stress and stress-related behavior. In the present study, we examined effects of an intracerebroventricular injection of the MC4 receptor agonist, Ac-[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH 4-10-NH2 (MT II), and the MC4 receptor inverse agonist, Agouti-related protein (AGRP), on dorsal raphe nucleus (DRN) serotonergic neurons and the locus coeruleus (LC) noradrenergic neurons, both of which are brain neuronal systems related to responses to stress. The firing rate of DRN serotonergic neurons was increased by MTII, while AGRP had a lack of effect on the firing rate of DRN serotonergic neurons. In comparison with the DRN, MTII significantly reduced the firing rate of LC noradrenergic neurons, while AGRP increased LC neuronal activity. These findings suggest that MC4 receptor ligands differently regulate serotonergic and noradrenergic neuronal systems. The MC4 receptor mediating multiple regulation on the monoaminergic neuronal system may, in part, relate to stress responses (anxiety and/or depressive behavior).

Agouti-Related Protein↗

PubMed2003

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.

Administration, Oral↗

PubMed2003

Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents.

The melanocortin subtype 4 (MC4) receptor has been postulated to be involved in stress and stress-related behavior. We made use of melanocortin MC4 receptor agonists and antagonist to investigate the relationship between the melanocortin MC4 receptor and stress related disorders. The nonspecific melanocortin receptor agonist alpha-melanocyte stimulating hormone (alpha-MSH) and the melanocortin MC4 receptor agonist, Ac-[Nle4,Asp5,D-Phe7,Lys10]alpha-MSH-(4-10)-NH2 (MT II) dose-dependently and significantly reduced the number of licking periods in the rat Vogel conflict test, suggesting that stimulation of the melanocortin MC4 receptor causes anxiogenic-like activity in rats. We synthesized a peptidemimetic melanocortin MC4 receptor selective antagonist, Ac-D-2Nal-Arg-2Nal-NH2 (MCL0020), which has high affinity for the melanocortin MC4 receptor with IC50 values of 11.63 +/- 1.48 nM, in contrast, the affinities for melanocortin MC1 and MC3 receptors were negligible. In addition, MCL0020 significantly attenuated the cAMP formation induced by alpha-MSH in COS-1 cells expressing the melanocortin MC4 receptor without affecting basal cAMP contents. Thus, we considered MCL0020 to be a selective melanocrotin MC4 receptor antagonist among melanocortin receptors. Restraint stress significantly reduced food intake in rats, and i.c.v. administration of MCL0020 dose-dependently and significantly attenuated restraint stress-induced anorexia without affecting food intake. Swim stress induced reduction in the time spent in the light area in the mouse light/dark exploration test, and MCL0020 significantly prevented it. Taken together our findings suggest that the melanocortin MC4 receptor might be related to stress-induced changes in behavior, and blockade of the melanocortin MC4 receptor may prevent stress-induced disorders such as anxiety.

Animals↗