The Pharmacon-Receptor-Effector Concept

Ariëns, E. J.; Beld, A.J.; Miranda, J. F. Rodrigues de; Simonis, A. M.

doi:10.1007/978-1-4684-0979-6_2

Cited by 49 publications

(27 citation statements)

References 71 publications

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“…Specific binding of Man-BSA for mature murine neutrophils and red blood cells is also shown in Fig. 1 (30,31). Similar data were observed when FDCP-1 cells were used as target cells.…”

Section: Resultssupporting

confidence: 75%

See 1 more Smart Citation

Characterization of membrane homing receptors in two cloned murine hemopoietic progenitor cell lines.

Matsuoka

Hardy²,

Tavassoli³

1989

J. Clin. Invest.

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“…Specific binding of Man-BSA for mature murine neutrophils and red blood cells is also shown in Fig. 1 (30,31). Similar data were observed when FDCP-1 cells were used as target cells.…”

Section: Resultssupporting

confidence: 75%

“…The displacement curve gives a typical sigmoid-shaped curve as a function ofthe concentration ofcold ligand (30,31). Similarly, cold Man-BSA, which has two binding components, one coinciding in affinity with that of Gal-BSA, can displace radiolabeled Gal-BSA with a similar sigmoid-shaped curve.…”

Section: Discussionmentioning

confidence: 99%

Characterization of membrane homing receptors in two cloned murine hemopoietic progenitor cell lines.

Matsuoka

Hardy²,

Tavassoli³

1989

J. Clin. Invest.

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“…The rationale for this lead discovery approach was reported earlier in a paper describing the design of the GH secretagogue MK-0677 (28). The concept that there are recurring structural units in many receptor ligands originated with Ariens et al (29), who noted the presence of double-ring structures in many biogenic amine antagonists which they suggested might bind in conserved accessory binding sites of receptors. More recently, Evans et al (30) termed these recurring units privileged structures and suggested their derivatization as a strategy to discover receptor ligands.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Berk²,

Rohrer³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

131

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A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 g/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054,522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.Somatostatin is widely distributed throughout the central nervous system and various endocrine tissues (1-3). Two biologically active forms of somatostatin are known, a 14-amino acid peptide and an N-terminal extended peptide with 28 amino acids (4 -6). Somatostatin has multiple functions, including modulation of growth hormone, insulin, glucagon, and gastric acid secretion (3, 7-10). Five somatostatin receptors (sst1-5) have been cloned and characterized (11)(12)(13)(14). All five receptors are members of the G protein-linked receptor family (15). Structure-function studies with a large number of peptidal analogs have shown that the Trp 8 -Lys 9 dipeptide of somatostatin is necessary for high-affinity binding (16) and have facilitated the development of potent analogs, including SMS 201-955 (Sandostatin or octreotide) which is clinically used for the treatment of acromegaly and certain endocrine tumors (17-19). We describe here strategies that were successful in designing small molecule subtype 2-selective agonists whose potencies on this receptor exceed somatostatin. Studies utilizing one of these subtype-selective somatostatin peptidomimetics, L-054,522, in both in vivo and in vitro experiments demonstate that somatostatin receptor subtype 2 (sst2) mediates the inhibition of growth hormone release from the rat anterior pituitary as well as glucagon from the rat pancreas. Insulin release is only inhibited at significantly higher concentrations of the compound. These results suggest possible therapeutic applications of selective sst2 agonists. Compound 4 was initially synthesized in a combinatorial library consisting of 20 diamines, 20 amino acids, and 79 amines. The diamines were linked to 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid functionalized Tentagel resin via urethane chemistry in a regiorandom way. 9-Fluorenylmethoxycarbonyl amino acids were coupled to the amine resins using standard 1,3-diisopropylcarbodiimide coupling. The 9-fluorenylmethoxycarbonyl groups were removed with piperidine and activated with p-nitrophenyl chloroformate before ...

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“…It has been appreciated for many years that certain molecular units have the capability to interact with diverse receptors, a phenomenon for which Evans et al (11) coined the phrase privileged structures. For example, structural templates such as benzodiazepines and 1,1-diphenylmethanes were known to be recurring structural features of some central nervous system drugs (12,13). A benzodiazepine core is present in the natural product cholecystokinin (CCK) antagonist asperlicin, and Evans et al (14) derivatized that part structure in their…”

mentioning

confidence: 99%

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

Patchett

Nargund

Tata

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

314

201

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The Pharmacon-Receptor-Effector Concept

Cited by 49 publications

References 71 publications

Characterization of membrane homing receptors in two cloned murine hemopoietic progenitor cell lines.

Characterization of membrane homing receptors in two cloned murine hemopoietic progenitor cell lines.

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

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