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)

Experimental details for the "Fmoc solid phase peptide synthesis" of somatostatin are described. The 9-fluorenylmethyloxycarbonyl group was rapidly and quantitatively cleaved by 55% piperidine in dimethylformamide and monitored (u.v.) manually. For a kinetic study, a centrifugal reactor with a photometric control system and reference cell was used at each stage. The symmetrical anhydride coupling reaction was rapid and either acetic anhydride or fluorescamine termination was incorporated to minimize formation of deletion peptides. Anchor-bond cleavage was effected with trifluoroacetic acid which simultaneously removed all the acid labile tert.-butyl side chain protecting groups. N alpha-9-fluorenylmethyloxycarbonyl peptides may be obtained by omitting the piperidine deprotection step after the last cycle of synthesis. From several syntheses, analytically pure di-S-protected somatostatin 14-peptide was obtained in 55-60% overall yield. The S-protecting groups were removed and the product was purified by gel filtration to give homogeneous dihydrosomatostatin (91%) yield. Oxidation of dihydrosomatostatin with potassium ferricyanide and purification by countercurrent distribution provided analytically pure homogeneous somatostatin.
 ...
PMID:Solid-phase peptide synthesis of somatostatin using mild base cleavage of N alpha-9-fluorenylmethyloxycarbonylamino acids. 610 95

Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine [corrected] GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50 = 3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of G H in a dose-dependent manner. Plasma insulin-like growth factor-I (IGF-I) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-I levels.
 ...
PMID:Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine [correction of pyrazolidinone-piperidine] growth hormone secretagogue. 1132 94

A novel synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin (DMJ) scaffold has been developed. This involved development of a route suitable for the strategic grafting of pharmacophoric tryptophan and lysine side chains to the nitrogen atom of the piperidine ring and to the primary hydroxyl group of DMJ, respectively. The novel peptidomimetics were found to bind with higher affinity to sst4 receptors than to sst5 receptors.
 ...
PMID:Synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin scaffold. 1620 3

While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural products, we discovered a reaction involving a rapid 6pi-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues. The electrocyclic reaction of the 1-azatriene system, a cyclization precursor, exhibited a substituent effect. Structure-reactivity studies showed that azaelectrocyclization, which usually proceeds in low yield at high temperatures, produced a quantitative yield in less than 5 min at room temperature. Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid-supports were applied to synthesize pyridine/indole alkaloid-type natural products. Additionally, we developed lysine-based labeling of biomolecules based on the rapid 6pi-azaelectrocyclization. Both DOTA as a metal chelating agent (either for MRI, PET, or other radiopharmaceutical purposes, e.g., SPECT with gamma emitters) as well as fluorescent groups were introduced efficiently and selectively into lysine residues within 10 min at concentrations as low as 10(-8) m. The DOTA-labeled somatostatin and glycoproteins were then radiometallated with (68)Ga to observe the receptor-mediated accumulation of somatostatin in pancreatic tissue. Furthermore, microPET visualized the oligosaccharide dependent circulatory residence of glycoproteins for the first time.
 ...
PMID:New strategy in synthetic biology: from enzyme inhibition and natural products synthesis to PET imaging by 6pi-azaelectrocyclization. 2034 8

An inner retinal microcircuit composed of dopamine (DA)-containing amacrine cells and melanopsin-containing, intrinsically photosensitive retinal ganglion cells (M1 ipRGCs) process information about the duration and intensity of light exposures, mediating light adaptation, circadian entrainment, pupillary reflexes, and other aspects of non-image-forming vision. The neural interaction is reciprocal: M1 ipRGCs excite DA amacrine cells, and these, in turn, feed inhibition back onto M1 ipRGCs. We found that the neuropeptide somatostatin [somatotropin release inhibiting factor (SRIF)] also inhibits the intrinsic light response of M1 ipRGCs and postulated that, to tune the bidirectional interaction of M1 ipRGCs and DA amacrine cells, SRIF amacrine cells would provide inhibitory modulation to both cell types. SRIF amacrine cells, DA amacrine cells, and M1 ipRGCs form numerous contacts. DA amacrine cells and M1 ipRGCs express the SRIF receptor subtypes sst(2A) and sst4 respectively. SRIF modulation of the microcircuit was investigated with targeted patch-clamp recordings of DA amacrine cells in TH-RFP mice and M1 ipRGCs in OPN4-EGFP mice. SRIF increases K(+) currents, decreases Ca(2+) currents, and inhibits spike activity in both cell types, actions reproduced by the selective sst(2A) agonist L-054,264 (N-[(1R)-2-[[[(1S*,3R*)-3-(aminomethyl)cyclohexyl]methyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]spiro[1H-indene-1,4'-piperidine]-1'-carboxamide) in DA amacrine cells and the selective sst4 agonist L-803,087 (N(2)-[4-(5,7-difluoro-2-phenyl-1H-indol-3-yl)-1-oxobutyl]-L-arginine methyl ester trifluoroacetate) in M1 ipRGCs. These parallel actions of SRIF may serve to counteract the disinhibition of M1 ipRGCs caused by SRIF inhibition of DA amacrine cells. This allows the actions of SRIF on DA amacrine cells to proceed with adjusting retinal DA levels without destabilizing light responses by M1 ipRGCs, which project to non-image-forming targets in the brain.
 ...
PMID:Parallel Inhibition of Dopamine Amacrine Cells and Intrinsically Photosensitive Retinal Ganglion Cells in a Non-Image-Forming Visual Circuit of the Mouse Retina. 2663 76