Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pancreatic polypeptide (PP-fold) family of peptides consists of the endocrine peptides, pancreatic polypeptide (PP) and peptide YY (PYY), and the neuroneally derived peptide, neuropeptide Y (NPY). All three peptides are found in the circulation, with PP found primarily in the pancreas and PYY found principally in the gut. NPY is released into the circulation from neuroneal stores in response to stress. These peptides have broad peripheral actions on a number of organs. Not surprisingly, PYY and PP are believed to play an important role in the function of the gastrointestinal tract while NPY is a potent vasconstrictor and may have effects on the gut through the enteric nervous system. In the brain, NPY has been implicated in anxiety and depression, feeding and obesity, memory retention, neuroneal excitability, endocrine function, and metabolism. Recent advances in the molecular biology of the receptors for these peptides have resulted in the identification of at least six receptor subtypes with varying peptide pharmacology. Compared to other G-protein coupled receptor families, the PP-fold peptide receptors exhibit a relatively low level of sequence identity. Further advances in the development of selective agonists and antagonists for individual receptor subtypes will be needed to understand further their role in physiological function.
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PMID:Multiple receptors for the pancreatic polypeptide (PP-fold) family: physiological implications. 957 48

Mice harboring random gene-trap insertions of a lacZ (beta-galactosidase)-neomycin resistance fusion cassette (beta-geo) were analyzed for expression in the hippocampus. In 4 of 15 lines reporter gene activity was observed in the hippocampal formation. In the obn line, enzyme activity was detected in the CA1-3 hippocampal subfields, in hpk expression was restricted to CA1, but in both lines reporter activity was also present in other brain regions. In the third line, kin, reporter activity was robustly expressed throughout the stratum pyrimidale of CA1-3, with only low-level expression elsewhere. The final line (glnC) displayed ubiquitous expression of the reporter and was not analyzed further. Fusion transcripts for the first three lines were characterized; all encode polypeptides with features of membrane-associated signalling proteins. The obn fusion identified a human cDNA (B2-1) encoding a pleckstrin homology (PH) domain, while hpk sequences matched the Epstein-Barr Virus (EBV) inducible G-protein coupled receptor, EBI-1. kin identified an alternative form of the abl-related nonreceptor tyrosine kinase c-arg. Electrophysiological studies on mice homozygous for the insertions revealed normal synaptic transmission, paired pulse facilitation and paired-pulse depression at Schaffer collateral-commissural CA1 synapses, and normal long-term potentiation (LTP) in obn and kin. hpk mice displayed an increase in hippocampal CA1 long-term potentiation (LTP), suggesting a role for this receptor in synaptic plasticity.
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PMID:Gene-trapping to identify and analyze genes expressed in the mouse hippocampus. 982 57

The study of tachykinin NK1 (substance P) receptor antagonists has emerged as a field of great promise due to accumulating evidence that NK1 antagonists offer possible new treatment options in therapeutic areas ranging from pain, emesis, and pulmonary disorders to depression and anxiety. It is hoped that the unique mechanism of action of these agents, which involves modulation of effects mediated by the interaction of the neuropeptide substance P with it's G-protein coupled receptor, will provide improvements over existing therapies. For this reason many pharmaceutical companies are engaged in intense research programs with the goal of bringing safe and effective new drugs to the market. To date a wealth of diverse NK1 antagonists have been discovered, several of which have been evaluated in clinical trials. Despite rich structural diversity in this area of medicinal chemistry a number of structural features are commonly shared amongst otherwise unrelated antagonists. This theme and others are covered with the aim of conveying recent successful approaches to the discovery of potent and selective nonpeptide NK1 antagonists. This review focuses mainly on reports appearing in the year 2001 and the first half of 2002.
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PMID:Medicinal chemistry of selective neurokinin-1 antagonists. 1287 Nov 73

Serotonin (5-HT) is involved in various physiological and pathological processes by interaction with 14 distinct receptor subtypes, grouped in seven classes of receptors (5-HT(1-7)) on the basis of amino acid sequence, pharmacology, and signal transduction pathways. The 5-HT(7)R is a G-protein coupled receptor with seven transmembrane domains. It was found by the application of molecular cloning and has been identified in rat, mouse, human, pig, and guinea pig. Although the biological functions of the 5-HT(7)Rs are poorly understood, preliminary evidence suggests that it may be involved in depression, control of circadian rhythms, and relaxation of vascular smooth muscles. For these reasons, the 5-HT(7)R has become a target for the development of novel drugs. This review will give a brief introduction of the pharmacology of 5-HT(7)R (molecular structure, distribution of 5-HT(7)R mRNA, localization of the 5-HT(7)R protein, functional correlates, and therapeutic potential) and a detailed survey of the 5-HT(7)R ligands, which have appeared in the literature in both papers and patents. Structure-activity relationships (SAR) of these ligands will also be described.
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PMID:Serotonin(7) receptors (5-HT(7)Rs) and their ligands. 1503 9

myo-Inositol (mI) is a key metabolic precursor to the phospoinositide (PI) metabolic pathway as a key component of central G-protein coupled receptor signaling systems, including several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors. High dose mI has also been shown to be clinically effective in the treatment of obsessive-compulsive disorder, as well as panic and depression, although its mechanism of action remains elusive. The current study aimed to investigate the possible modulatory role of mI versus fluoxetine or imipramine pretreatments on serotonin-2A receptor (5HT2A-R) and muscarinic acetylcholine receptor (mAChR) function and binding in in vitro systems. After pretreating human neuroblastoma cells with different concentrations of mI, fluoxetine, or imipramine, receptor function was measured by second messenger [3H]-IPx accumulation and [35S]-GTPgammaS binding to G alpha(q) protein. Total [3H]-mI uptake into cells was measured, as well as specific receptor binding to determine receptor binding after the pretreatments. Results suggest that mI reduces 5HT2A-R function at the receptor-G protein level. While fluoxetine also reduced 5HT2A-R function, but to a lesser degree, imipramine increased 5HT2A-R function, which may explain why mI seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders. In addition mI, and at high concentrations fluoxetine and imipramine, also reduces mAChR function. Furthermore the results suggest that the attenuating effect of mI on mAChRs is partially dependent on the PI metabolic pathway. The data provide novel information on understanding the mechanism of action of mI in depression and related anxiety disorders and added to the evidence suggesting a role for the cholinergic system in the pathophysiology of depression.
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PMID:Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells. 1521 6

Bergmann glial cells (BGC) enclose the synapses of Purkinje neurons (PN) and interneurons in the molecular layer of the cerebellar cortex. During synaptic transmission, glutamate evokes inward currents in the glia by activation of Ca2+-permeable aminohydroxymethylisoxazole propionic acid receptors (AMPAR) and electrogenic transporters. We describe the plasticity of BGC currents during paired-pulse and repetitive stimulation of parallel fibers in cerebellar slices. Paired-pulse facilitation (PPF) of BGC AMPAR currents was 4-fold, twice that of PN PPF. Experiments with a low-affinity AMPAR antagonist showed an increase in extrasynaptic glutamate concentration during the second pulse of the pair. PPF of glial transporter currents was 1.8-fold, similar to synaptic PPF. Tetanic stimulation revealed that facilitation of BGC AMPAR currents is not sustained during high-frequency stimulation, and substantial depression is observed after a few pulses. Consequently, Ca2+ influx through glial AMPARs would initially be facilitated but subsequently depressed, generating a transient Ca2+ influx in response to a sustained tetanus. This pattern of plasticity may be important in enabling Bergmann glial cell processes to detect and support synapses with high-frequency input. Finally, a new current was observed in BGC during repetitive stimulation. It was blocked by NBQX and intracellular GDP-beta-S, increased by glutamate uptake inhibition, had PPF similar to synaptic PPF, and was unaffected by an inhibitor of fast glial AMPAR currents. The evidence suggests that activation of neuronal AMPARs causes the release of a paracrine messenger to activate a G-protein coupled receptor in the BGC.
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PMID:Short-term plasticity of Bergmann glial cell extrasynaptic currents during parallel fiber stimulation in rat cerebellum. 1607 33

Since its discovery, 5-hydroxytryptamine, more usually called serotonin, has been an elusive candidate as a major mood regulator. This capacity gives it a great importance in the treatment of depression. It is within this framework that our work takes place, as it is related more particularly to a new therapeutic class whose leader is agomelatine. This compound binds to the melatoninergic receptors and to the serotoninergic 5-HT2c receptor, giving rise to the MASSA concept (Melatonin Agonist and Selective Serotonin Antagonist). Like the majority of the serotoninergic receptors, the sub-type 5-HT2c is a G-protein coupled receptor (GPCR). The three-dimensional structure of 5-HT2c is not experimentally known, and we thus resorted to comparative homology modelling to build a model allowing us to study its interactions with agomelatine.
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PMID:Homology modelling of the serotoninergic 5-HT2c receptor. 1691 76

Corticotrophin Releasing Hormone (CRH) is a primary hormone in the fight or flight response targeting a membrane bound G-protein coupled receptor (GPCR). Many people worldwide stand to benefit by the development of CRH agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimer's, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR targeted therapeutic. Several key proteins influence the complex and intrinsic regulation of CRH, including its receptors (CRHR), of which 3 types have been categorised, CRHR(1), CRHR(2), CRHR(3), each containing active and inactive splice variants. Additionally, the CRH binding protein (CRHBP) is believed to moderate the effects of CRH at the receptor, whether it is as a molecular mop, or a delivery vessel, or both, is still being investigated. Homology based receptor modelling is a technique that has only recently become available with the crystallisation of bovine rhodopsin (a GPCR), [1] and the application of this technique to the CRH receptors is still in the early stages of development. Therefore, the medicinal chemist has previously had to rely on ligand-based strategies, specifically, the development of pharmacophores. Thus, an extensive number of both CRH peptide analogues and small ligands that show nanomolar antagonism have been developed with SAR libraries being integral to the iterative drug design process.
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PMID:Corticotropin releasing hormone--a GPCR drug target. 1726 35

The advance of functional genomics revealed the superfamily of G-protein coupled receptors (GPCRs). Hundreds of GPCRs have been cloned but many of them are orphan GPCRs with unidentified ligands. The first identified orphan GPCR is the opioid receptor like orphan receptor, ORL1. It was cloned in 1994 during the identification of opioid receptor subtypes and was de-orphanized in 1995 by the discovery of its endogenous ligand, nociceptin or orphanin FQ (N/OFQ). This receptor was renamed as N/OFQ peptide (NOP) receptor. Several selective ligands acting at NOP receptors or other anti-N/OFQ agents have been reported. These include N/OFQ-derived peptides acting as agonists (cyclo[Cys(10),Cys(14)]N/OFQ, [Arg(14), Lys(15)]N/OFQ, [pX]Phe(4)N/OFQ(1-13)-NH(2), UFP-102, [(pF)Phe(4),Aib(7), Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)) or antagonists (Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2), [Nphe(1)]N/OFQ(1-13)-NH(2), UFP-101, [Nphe(1), (pF)Phe(4),Aib(7),Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)), hexapeptides, other peptide derivatives (peptide III-BTD, ZP-120, OS-461, OS-462, OS-500), non-peptide agonists (NNC 63-0532, Ro 64-6198, (+)-5a compound, W-212393, 3-(4-piperidinyl)indoles, 3-(4-piperidinyl) pyrrolo[2,3-b]pyridines) and antagonists (TRK-820, J-113397, JTC-801, octahydrobenzimidazol-2-ones, 2-(1,2,4-oxadiazol-5-yl)-1 H-indole, N-benzyl-D-prolines, SB-612111), biostable RNA Spiegelmers specific against N/OFQ, and a functional antagonist, nocistatin. Buprenorphine and naloxone benzoylhydrazone are two opioid receptor ligands showing high affinity for NOP receptors. NOP receptor agonists might be beneficial in the treatment of pain, anxiety, stress-induced anorexia, cough, neurogenic bladder, edema, drug dependence, and, less promising, in cerebral ischemia and epilepsy, while antagonists might be of help in the management of pain, depression, dementia and Parkinsonism. N/OFQ is also involved in cardiovascular, gastrointestinal and immune regulation. Altered plasma levels of N/OFQ have been reported in patients with various pain states, depression and liver diseases. This review summarizes the pharmacological characteristics of, and studies with, the available NOP receptor ligands and their possible clinical implications.
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PMID:Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. 1726 36

Derived from proopiomelanocortin by proteolytic processing, melanocortins have been implicated in a wide range of physiological processes. Melanocortins exert their physiological effects by binding to specific receptors on the surface of cell membranes. To date, five subtypes of melanocortin receptors (MC1-MC5) have been identified, all of which are G-protein coupled receptor whose activation leads to increase in intracellular cyclic 3',5'-adenosine monophosphate formation. Of these, the MC4 receptor is expressed predominantly throughout the central nervous system, particularly, in areas related to stress responses and emotional states. Expression of the MC4 receptor is regulated by stress exposure. Reports also indicate that stimulation of the MC4 receptor activates the hypothalamus-pituitary-adrenal axis, and that the MC4 receptor mediates stress-related behaviors and anxiety in rodents. Recently developed selective MC4 receptor antagonists have demonstrated antidepressant and anxiolytic effects in several animal models of depression and anxiety. MC4 receptor antagonists are effective, particularly under conditions of high stress, which may be consistent with the etiology of depression and anxiety. This review describes the involvement of the MC4 receptor in stress response and discusses the potential value of MC4 receptor antagonists for the treatment of stress-related disorders such as depression and anxiety.
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PMID:Melanocortin-4 receptor antagonists for the treatment of depression and anxiety disorders. 1758 35


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