Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Utilizing NNC 26-9100 (11) as a structural lead, a variety of nonpeptide derivatives of somatostatin were synthesized and evaluated for sst2 and sst4 receptor binding affinity. A novel thiourea scaffold was utilized to attach (1) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mimic Phe7, and (3) a primary amine or other basic group to mimic the Lys9 residue of somatostatin. Displacement studies were carried out using membranes from cell lines expressing ssts [BHK cells (sst4) and HEK 293 cells (sst2)] utilizing [125I]Tyr11-SRIF as the radioligand. Several thioureas (11, 38, 39, 41, and 42) and the urea 66 exhibited Ki values of less than 100 nM. The thioureas 11 (Ki = 6 nM) and 41 (Ki = 16 nM) and the urea 66 (Ki = 14 nM) are believed to be the most potent nonpeptide sst4 agonists known. Since the thiourea 11 and the urea 66 exhibit high sst4 selectivity, these novel nonpeptide derivatives may be useful tools for studying the sst4 receptor. Studies are currently in progress to evaluate the therapeutic potential of NNC 26-9100 (11) in the treatment of glaucoma.
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PMID:Nonpeptide somatostatin agonists with sst4 selectivity: synthesis and structure-activity relationships of thioureas. 982 40

At the present time only two long-acting somatostatin (SS) analogs, octreotide and lanreotide, are commonly used in the routine therapy. Both analogs have a high affinity mainly to a somatostatin receptor subtype 2 (SSTR2). The established indications for SS analogs treatment include acromegaly, neuroendocrine tumors of the pancreas and gastrointestinal tract, and some gastro-enterologic diseases (pancreatitis, gastrointestinal bleedings, refractory diarrheas, pancreatic and intestinal fistulas). The recent investigations allow to predict the enlargement of therapeutic applications of SS analogs. It concerns pituitary tumors other than somatotropinoma, tumors of other endocrine glands like thyroid and adrenal gland, as well as some non-endocrine tumors. The progress depends on the introduction of new SS analogs with high affinity for SS receptor subtypes other than SSTR2, because some tumors present the high expression of SSTR1 (e.g. prostatic cancers) or SSTR5 (e.g. colonic cancers). Great hopes are connected with the coupling of SS analogs with the radioactive isotopes or non-radioactive cytotoxic agents to destruct the neoplastic cells highly expressing the specific subtypes of SS receptors. The pre- or postoperative in vivo imaging of SS receptors by means of the receptor scintigraphy, as well as the post-operative identification of SS receptor subtypes in the excised tumor tissues using immunohistochemistry, should play an important role in the prediction of the effects of SS analog treatment. Beside oncology, new therapeutic applications of SS analogs could be presumed among others in ophthalmology; it concerns the treatment of progressive Graves-Basedow ophtalmopathy, diabetic retinopathy, glaucoma and corneal diseases connected with corneal vascularization.
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PMID:Perspectives of new potential therapeutic applications of somatostatin analogs. 1274 27

Transient retinal ischemia induces loss of retinal ganglion cells, supporting the hypothesis that ischemic conditions contribute to the induction and progression of glaucoma. However, after 60 min of ischemia, also amacrine cells are lost from the inner nuclear layer. The main goal was to determine the relative vulnerability of various amacrine subpopulations by measuring the levels of transcripts that are known to be specifically expressed by different amacrine subpopulations. A 60-min ischemic period was administered to the rat eye by raising the intraocular pressure, followed by a reperfusion period lasting between 2 h and 4 weeks. Total RNA was isolated from the whole retina and expression levels were assessed by real-time quantitative polymerase chain reaction (qPCR). Retinal ischemia/reperfusion has differential effects on the levels of the various transcripts. Three main patterns of changes were identified. (i) A gradual decrease of transcript level without recovery was observed for parvalbumin; this transcript is expressed by the glycinergic AII cells. (ii) A gradual reduction to different levels at 72 h of reperfusion followed by a partial or complete recovery (glycine transporter 1, glutamate decarboxylase, calretinin, and several other transcripts). The glycinergic amacrine cell markers recovered to 65-75% of the control level, while the main GABAergic markers had completely recovered at 4 weeks. (iii) No significant changes of transcript levels were found for markers of several smaller GABAergic subpopulations [including substance P (Tac1), somatostatin, and others]. Expression levels of photoreceptor-, horizontal cell-, and bipolar cell-specific transcripts were not altered. These patterns were confirmed by a cluster analysis of the data. Based on gene expression levels, it may be concluded that amacrine cells are vulnerable to ischemic insults and that the glycinergic amacrine cells are relatively more sensitive to ischemia than the GABAergic population. In particular, the extensive loss of the parvalbumin-containing AII amacrine cells, which serve in the rod pathway, may have functional implications for vision under scotopic conditions. In the accompanying paper [F. Dijk and W. Kamphuis, An immunocytochemical study on specific amacrine subpopulations in the rat retina after ischemia, Brain Res. (2004).], the results are evaluated at the protein level by immunostaining for a selection of the amacrine cell markers.
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PMID:Differential effects of ischemia/reperfusion on amacrine cell subtype-specific transcript levels in the rat retina. 1548 81

Ischemia is a primary cause of neuronal death in retinal diseases. The repertoire of expressed transmitter receptors would determine the neurons' responses to ischemic damage, and peptidergic receptors may be involved. With a new in vitro model of the ischemic mouse retina, we investigated whether an altered expression of somatostatin receptors could modulate retinal responses to ischemia. We used retinas of somatostatin receptor 1 (sst(1)) knock out (KO) mice, where sst(2) are over-expressed and over-functional, and of sst(2) KO mice. TUNEL analysis of ischemic retinas showed a marked reduction of cell death in sst(1) KO retinas, while there were no differences between wild-type (WT) and sst(2) KO retinas. In addition, caspase-3 mRNA expression was also reduced in sst(1) KO as compared to WT retinas. An immunohistochemical analysis demonstrated that different cell populations responded differently to the ischemic insult, and that the persistence of some immunohistochemical markers was greater in sst(1) KO than in WT or in sst(2) KO retinas. In particular, rod bipolar cell survival was markedly improved in sst(1) KO retinas, while it was dramatically decreased in sst(2) KO retinas. Furthermore, consistent with a role of glutamate excitotoxicity in ischemia-induced neuronal death, retinal glutamate release was observed to increase under ischemic conditions, but this increase was significantly reduced in sst(1) KO retinas. These observations demonstrate that an increased presence of functional sst(2) protects against retinal ischemia, thus implementing the background for the use of sst(2) analogs in therapies of retinal diseases such as glaucoma or diabetic retinopathy.
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PMID:Changes in neuronal response to ischemia in retinas with genetic alterations of somatostatin receptor expression. 1742 70

Dopamine (DA) and DA receptors (DR) have been extensively studied in the central nervous system (CNS), but their role in the periphery is still poorly understood. Here we summarize data on DA and DRs in the eye, cardiovascular system and endocrine pancreas, three districts where DA and DA-related drugs have been studied and the expression of DR documented. In the eye, DA modulates ciliary blood flow and aqueous production, which impacts on intraocular pressure and glaucoma. In the cardiovascular system, DA increases blood pressure and heart activity, mostly through a stimulation of adrenoceptors, and induces vasodilatation in the renal circulation, possibly through D1R stimulation. In pancreatic islets, beta cells store DA and co-release it with insulin. D1R is mainly expressed in beta cells, where it stimulates insulin release, while D2R is expressed in both beta and delta cells (in the latter at higher level), where it inhibits, respectively, insulin and somatostatin release. The formation of D2R-somatostatin receptor 5 heteromers (documented in the CNS), might add complexity to the system. DA may exert both direct autocrine effects on beta cells, and indirect paracrine effects through delta cells and somatostatin. Bromocriptine, an FDA approved drug for diabetes, endowed with both D1R (antagonistic) and D2R (agonistic) actions, may exert complex effects, resulting from the integration of direct effects on beta cells and paracrine effects from delta cells. A full comprehension of peripheral DA signaling deserves further studies that may generate innovative therapeutic drugs to manage conditions such as glaucoma, cardiovascular diseases and diabetes.
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PMID:Dopamine outside the brain: The eye, cardiovascular system and endocrine pancreas. 3129 15