ABSTRACT
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Subject(s)
Amides/chemistry , Amides/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Brain/drug effects , Brain/metabolism , Cattle , Computational Biology , Humans , Ligands , Models, Molecular , Molecular Structure , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Sulfur/chemistryABSTRACT
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
Subject(s)
Amides/pharmacology , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Anilides/chemistry , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Humans , Molecular Structure , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
Melanin-concentrating hormone (MCH) is a critical hypothalamic anabolic neuropeptide, with key central and peripheral actions on energy balance regulation. The actions of MCH are, so far, known to be transduced through two seven-transmembrane-like receptor paralogues, named MCH1R and MCH2R. MCH2R is not functional in rodents. MCH1R is an important receptor involved in mediating feeding behaviour modulation by MCH in rodents. Pharmacological antagonism at MCH1R in rodents diminishes food intake and results in significant and sustained weight loss in fat tissues, particularly in obese animals. Additionally, MCH1R antagonists have been shown to have anxiolytic and antidepressant properties. The purpose of this review is to highlight the recent numerous pieces of evidence showing that pharmacological blockade at MCH1R could be a potential treatment for obesity and its related metabolic syndrome, as well as for various psychiatric disorders.
Subject(s)
Affect/physiology , Energy Metabolism/physiology , Hypothalamic Hormones/physiology , Melanins/physiology , Pituitary Hormones/physiology , Animals , Eating/physiology , Humans , Hypothalamic Hormones/antagonists & inhibitors , Hypothalamic Hormones/metabolism , Melanins/antagonists & inhibitors , Melanins/metabolism , Neurobiology , Pituitary Hormones/antagonists & inhibitors , Pituitary Hormones/metabolism , Receptors, Somatostatin/antagonists & inhibitors , Receptors, Somatostatin/metabolismABSTRACT
The human 7-transmembrane receptor GPR7 has sequence similarity to opioid and somatostatin receptors, and can be activated by the recently discovered neuropeptides NPB and NPW. This receptor is highly expressed in the nervous system, with suggested roles in neuroendocrine events and pain signaling. In this study, we investigated whether the GPR7 receptor is expressed in the peripheral nervous system under normal and pathological conditions. A low level of GPR7 receptor was observed in myelin-forming Schwann cells in both normal human and rat nerve, and in primary rat Schwann cell cultures. Peripheral nerve samples taken from patients exhibiting inflammatory/immune-mediated neuropathies showed a dramatic increase of GPR7 receptor expression restricted to myelin-forming Schwann cells. Complementary animal models of immune-inflammatory and ligation-induced nerve injury and neuropathic pain similarly exhibited an increased myelin-associated expression of GPR7 receptor. These results suggest a relationship between the pathogenesis of inflammatory/immune-mediated neuropathies, GPR7 receptor expression, and pain transmission.
Subject(s)
Neuralgia/metabolism , Neuritis/metabolism , Peripheral Nervous System Diseases/metabolism , Receptors, Neuropeptide/genetics , Schwann Cells/metabolism , Adult , Aged , Animals , Biopsy , Cells, Cultured , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Female , Humans , Ligation , Male , Middle Aged , Myelin Sheath/metabolism , Neuralgia/physiopathology , Neuritis/physiopathology , Peripheral Nervous System Diseases/physiopathology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled , Receptors, Neuropeptide/biosynthesis , Sural Nerve/metabolism , Sural Nerve/physiopathology , Up-Regulation/physiologyABSTRACT
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, which centrally regulates food intake and stress. MCH induces food intake in rodents and, more generally, acts as an anabolic signal in energy regulation. In addition, MCH seems to be activatory on the stress axis. Two receptors for MCH in humans have very recently been characterised, namely, MCH-R1 and MCH-R2. MCH-R1 has received considerable attention, as potent and selective antagonists acting at that receptor display anxiolytic, antidepressant and/or anorectic properties. Feeding and affective disorders are both debilitating conditions that have become serious worldwide health threats. There are as yet no efficient and/or safe cures that could contain the near-pandemia phenomen of both diseases. Thus, the discovery of MCH-R1 antagonists may lead to the development of valuable drugs to treat obesity, anxiety and depressive syndromes. In addition, it opens wide avenues to probe additional functions of the peptide, both in the brain and in the peripheral nervous system.
Subject(s)
Brain/metabolism , Eating/physiology , Hypothalamic Hormones/physiology , Melanins/physiology , Pituitary Hormones/physiology , Stress, Physiological/physiopathology , Amino Acid Sequence , Animals , Appetite/drug effects , Appetite/physiology , Circadian Rhythm , Dogs , Eating/drug effects , Energy Intake/drug effects , Energy Intake/physiology , Energy Metabolism , Feeding and Eating Disorders/drug therapy , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/physiopathology , Ferrets , Humans , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiopathology , Mice , Molecular Sequence Data , Pineal Gland/drug effects , Pineal Gland/physiopathology , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiopathology , Primates , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Pituitary Hormone/drug effects , Receptors, Pituitary Hormone/physiology , Stress, Physiological/drug therapy , Stress, Physiological/epidemiologyABSTRACT
Apelin peptides have recently been identified to be the endogenous ligands for the G protein-coupled receptor APJ. However, little is known about the physiological roles of this ligand-receptor pairing. In the present study we investigated the pharmacology of several apelin analogues at the human recombinant APJ receptor using radioligand binding and functional assays. This has led to the identification of key residues in the apelin peptide required for functional potency and binding affinity through structure-activity studies. In particular, we have identified that replacement of leucine in position 5, or arginine in position 2 and 4 of the C-terminal apelin peptide, apelin-13, resulted in significant changes in pharmacology. We also investigated the detailed localization of pre-proapelin and APJ receptor mRNA in a wide range of human, rat and mouse tissues using quantitative RT-PCR, and carried out a detailed immunohistochemical study of the distribution of the APJ receptor in rat brain and spinal cord. Interestingly, the APJ receptor was not only co-localized in white matter with GFAP in the spinal cord, but was also clearly localized on neurones in the brain, suggesting that this receptor and its peptide may be involved in a wide range of biological process yet to be determined.
Subject(s)
Carrier Proteins/chemistry , Carrier Proteins/metabolism , Receptors, Dopamine D2/chemistry , Receptors, Dopamine D2/metabolism , Receptors, G-Protein-Coupled , Adipokines , Amino Acid Substitution , Animals , Apelin , Apelin Receptors , Binding, Competitive/physiology , Blotting, Western , Brain/metabolism , Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Cell Line , Cyclic AMP/metabolism , Fluorometry , Humans , Immunohistochemistry , Intercellular Signaling Peptides and Proteins , Ligands , Mice , Mutagenesis, Site-Directed , Organ Specificity , Protein Binding/physiology , Radioligand Assay , Rats , Receptors, Dopamine D2/genetics , Reverse Transcriptase Polymerase Chain Reaction , Spinal Cord/metabolism , Structure-Activity RelationshipABSTRACT
The neuropeptides orexin-A and orexin-B are produced in neurons of the lateral hypothalamic area and have been implicated to be involved in the regulation of food/water intake and sleep-wake control. The orexins act at two different G-protein-coupled orexin receptors (OX-R1 and OX-R2) that are derived from separate genes and expressed differentially throughout the central nervous system. In the present study, we have used a polyclonal antipeptide antiserum to analyse in detail the distribution of OX-R1-immunoreactive neurons in the rat hypothalamus. In order to identify the chemical mediators of orexin action in the hypothalamus, the OX-R1-containing neurons were characterized with regard to the content of peptides shown previously to affect ingestive and drinking behaviour. Neurons containing OX-R1 immunoreactivity were widely distributed in the hypothalamus with cell bodies located in the suprachiasmatic, periventricular, paraventricular (both magno- and parvocellular division), supraoptic, arcuate, ventromedial, dorsomedial and tuberomammillary nuclei and the lateral hypothalamic area. In magnocellular neurons of the paraventricular and supraoptic nuclei, OX-R1 immunoreactivity was seen in both vasopressin- and oxytocin-containing neurons. OX-R1 immunoreactivity was demonstrated in vasopressin and vasoactive intestinal polypeptide (VIP) neurons of the suprachiasmatic nucleus, in somatostatin neurons of the periventricular nucleus and in corticotropin-releasing hormone (CRH) neurons of the parvocellular paraventricular nucleus. In the arcuate nucleus, OX-R1 immunoreactivity was present in neuropeptide Y (NPY) and agouti-related peptide (AGRP) neurons of the ventromedial part as well as in proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons of the ventrolateral division. In the lateral hypothalamic area, OX-R1 immunoreactivity was demonstrated in melanin-concentrating hormone (MCH)- and orexin-containing neurons. In the hypothalamic tuberomammillary nucleus, OX-R1-immunoreactivity was shown in many histamine-containing neurons. The results support the idea that orexins have important actions on hypothalamic neurons that control food intake and fluid balance, but also that orexins may regulate other neuroendocrine systems.
