Somatostatin analogs with selected biologic activities

Brown, Marvin; Rivier, Jean; Vale, Wylie

doi:10.1016/s0026-0495(76)80178-3

Cited by 28 publications

(21 citation statements)

References 3 publications

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“…Certain analogues of somatostatin have been suggested to exert selective hormone-suppressive effects when their doseeffect relationships were studied in experimental animals, e.g., analogues with selective suppression of growth hormone, 16 insulin 37 or glucagon 38 servations provided no evidence for selective hormone suppression by the analogue.…”

Section: Discussionmentioning

confidence: 99%

“…5 Soma-(phe 6 , phe 7 , trp 8 , phe", and lys 9 ) was involved in receptor tostatin delays the development of ketosis during insulin dep-binding and activation. 16 A recently synthetized octapeptide rivation; 6 ' 7 it decreases growth hormone concentrations, 8 which of somatostatin (201-995) has been demonstrated in rhesus are increased during poor diabetes control 9 and which may monkeys to be 45 times more effective than native somatoworsen metabolic control in diabetes. 10 Despite these poten-statin in suppressing growth hormone secretion, 1.3 times tial benefits of somatostatin as a therapeutic agent in diabetic more potent in inhibiting insulin release, and 11 times more subjects, the need for continuous infusion, due to its short active in suppressing plasma glucagon levels.…”

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confidence: 99%

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Reduced Postprandial Hyperglycemia After Subcutaneous Injection of a Somatostatin-Analogue (SMS 201-995) in Insulin-dependent Diabetes Mellitus

1985

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The effect of a new octapeptide analogue of somatostatin (SMS 201-995) on blood glucose and gut hormone levels was studied in 10 C-peptide-negative, insulin-dependent diabetic (IDDM) subjects. On separate days, either 50 or 100 micrograms SMS or placebo was s.c. injected simultaneously with an identical insulin dose 30 min before a mixed meal. Postprandial blood glucose decreased after 100 micrograms SMS s.c. within 30 min from 8.9 +/- 0.7 to 7.8 +/- 0.6 mmol/L (P less than 0.001) and remained at similar levels during 180 min. In contrast, postprandial blood glucose concentration increased after placebo from 9.9 +/- 0.8 to 13.8 +/- 0.9 mmol/L (SMS versus placebo P less than 0.001). Plasma glucagon decreased rapidly after SMS to the limit of detection (P less than 0.001) and remained lowered during 180 min; in contrast, glucagon levels increased after the meal during the placebo study (SMS versus placebo P less than 0.001). Plasma growth hormone concentrations were significantly lower after SMS than after placebo (P less than 0.05). SMS abolished completely the postprandial increase in plasma gastrin and pancreatic polypeptide (PP) concentrations. Plasma free fatty acid (FFA) and triglyceride concentrations decreased after SMS, reaching significantly lower levels than after placebo (P less than 0.05 and P less than 0.01), respectively). Plasma SMS concentration increased rapidly after s.c. administration of SMS; its appearance preceded that of plasma free insulin after s.c. insulin injection. Fifty micrograms SMS was similarly effective as 100 micrograms in decreasing blood glucose, triglycerides, glucagon, and gut hormone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reduced Postprandial Hyperglycemia After Subcutaneous Injection of a Somatostatin-Analogue (SMS 201-995) in Insulin-dependent Diabetes Mellitus

1985

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“…However, deletion of Lys 4 -Asn 5 results in 3 with very high potency to inhibit GH and insulin while inactive at inhibiting glucagon secretion. [29][30][31]52 Deletion of the additional Ser 13 results in 4 with high binding affinity at sst 2 and sst 4 , moderate binding affinity at sst 3 40 It was therefore hypothesized that the same substitution in an analogue shortened by two residues would retain such selectivity. The fact that 5 is essentially inactive at all of the receptors suggests that the scaffold of CH-275 is unique and necessary for both sst 1 affinity and selectivity.…”

Section: >1kmentioning

confidence: 99%

“…Systematically increasing the size of the bridging ring going from 20-atom-membered rings (25) to 26-atom-membered rings (26)(27)(28)(29)(30) ultimately led to 31 with a binding affinity comparable to that of the parent CH-288. It is noteworthy that two analogues (26 and 27) with the same number of atoms in the cycle yet with the lactam bridge shifted by one methylene group (Asp 7 to Orn 12 in 26 versus Glu 7 to Dab 12 in 27) differ in their binding affinities for sst 1 ; 27 shows at least 5 times greater binding affinity at sst 1 than 26.…”

Section: >1kmentioning

confidence: 99%

Somatostatin Receptor 1 Selective Analogues: 3. Dicyclic Peptides

et al. 2004

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The binding affinity of short chain somatostatin (SRIF) analogues at the five human SRIF receptors (sst) was determined to identify sterically constrained somatostatin receptor subtype 1 (sst(1)) selective scaffolds. Des-AA(1,2,4,13)-[d-Trp(8)]SRIF (2) retained high binding affinity at all receptors but sst(1), Des-AA(1,2,4,5)-[d-Trp(8)]SRIF (3) at sst(4) and sst(5), and Des-AA(1,2,4,5,13)-[d-Trp(8)]SRIF (4) at sst(2) and sst(4) (AA = amino acid). Des-AA(1,2,4,12,13)-[d-Trp(8)]SRIF (6) was potent and sst(4)-selective (>25-fold); Des-AA(1,2,5,12,13)-[d-Trp(8)]SRIF (7) and Des-AA(1,2,4,5,12,13)-[d-Trp(8)]-SRIF (9, ODT-8) were most potent at sst(4) and moderately potent at all other receptors. Dicyclic SRIF agonists of the sst(1)-selective Des-AA(1,5)-[Tyr(2),d-Trp(8),IAmp(9)]SRIF, (14, sst(1) IC(50) = 14 nM) were prepared in which a lactam bridge introduced additional conformational constraint (IAmp = 4-(N-isopropyl)-aminomethylphenylalanine). Cyclo(7-12)Des-AA(1,5)-[Tyr(2),Glu(7),d-Trp(8),IAmp(9),hhLys(12)]SRIF (31) (sst(1) IC(50) = 16 nM) and cyclo(7-12) Des-AA(1,2,5)-[Glu(7),d-Trp(8),IAmp(9),m-I-Tyr(11),hhLys(12)]SRIF (45) (sst(1) IC(50) = 6.1 nM) had equal or improved affinities over that of the parent 14. Binding affinity was decreased in all other cases with alternate bridging constraints such as cyclo (6-11), cyclo (6-12), and cyclo (7-11). Compound 45 is an agonist (EC(50) = 8.8 nM) in the adenylate cyclase assay.

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“…Several SS analogs with either a higher potency in suppressing insulin and glucagon secretion [D-Trps]-SS [l] or a greater effect for inhibition of glucagon than insulin [DC~S'~]-SS [2] and [DTrpS D-C~S'~]-SS [3,4] have now been developed. In the course of a study designed to compare the relative efficacies of the foregoing analogs as glucagon suppressants in alloxan diabetic dogs, it was noted that plasma samples were less turbid after a subcutaneous injection of the peptides than after a saline control.…”

Section: Introductionmentioning

confidence: 99%