Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors

Karoly Gulya; John T. Pelton; Victor J. Hruby; Henry I. Yamamura

doi:10.1016/0024-3205(86)90574-6

Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors

Karoly Gulya
, John T. Pelton
, Victor J. Hruby
, Henry I. Yamamura

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

Abstract

A series of cyclic conformationally restricted penicillamine containing somatostatin octapeptide analogues have been prepared by standard solid phase synthetic techniques and tested for their ability to inhibit specific [¹²⁵I]CGP 23,996 (des-Ala¹-,Gly²-[desamino-Cys³Tyr¹¹]-dicarba^3,14- somatostatin), [³H]naloxone or [³H]DPDPE ([D-Pen²-D-Pen⁵]enkephalin) binding in rat brain membrane preparations. We now report structure-activity relationship studies with the syntheis of our most potent and selective mu opioid receptor compound DPheCysTyrDTrpOrnThrPenThrNH₂, which we refer to as Cys²Tyr³Orn⁵Pen⁷-amide. While this octapeptide exhibited high affinity (IC₅₀ = 2.80 nM) for an apparently single population of binding sites (n_H = 0.89 ± 0.1) and exceptional selectivity for mu opioid receptos with an IC₅₁(DPDPE)/IC₅₀ (naloxone) ratio of 4,829, it also displayed very low affinity for somatostatin receptors (IC₅₀ = 22,700 nM). Thus, Cys²Tyr³Orn⁵ Pen⁷-amide may be the ligand of choice for further characterization of mu opioid receptors and for examining the physiological role of this class of receptors.

Original language	English (US)
Pages (from-to)	2221-2229
Number of pages	9
Journal	Life Sciences
Volume	38
Issue number	24
DOIs	https://doi.org/10.1016/0024-3205(86)90574-6
State	Published - Jun 16 1986
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Pharmacology, Toxicology and Pharmaceutics

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10.1016/0024-3205(86)90574-6

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title = "Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors",

abstract = "A series of cyclic conformationally restricted penicillamine containing somatostatin octapeptide analogues have been prepared by standard solid phase synthetic techniques and tested for their ability to inhibit specific [125I]CGP 23,996 (des-Ala1-,Gly2-[desamino-Cys3Tyr11]-dicarba3,14- somatostatin), [3H]naloxone or [3H]DPDPE ([D-Pen2-D-Pen5]enkephalin) binding in rat brain membrane preparations. We now report structure-activity relationship studies with the syntheis of our most potent and selective mu opioid receptor compound DPheCysTyrDTrpOrnThrPenThrNH2, which we refer to as Cys2Tyr3Orn5Pen7-amide. While this octapeptide exhibited high affinity (IC50 = 2.80 nM) for an apparently single population of binding sites (nH = 0.89 ± 0.1) and exceptional selectivity for mu opioid receptos with an IC51(DPDPE)/IC50 (naloxone) ratio of 4,829, it also displayed very low affinity for somatostatin receptors (IC50 = 22,700 nM). Thus, Cys2Tyr3Orn5 Pen7-amide may be the ligand of choice for further characterization of mu opioid receptors and for examining the physiological role of this class of receptors.",

author = "Karoly Gulya and Pelton, \{John T.\} and Hruby, \{Victor J.\} and Yamamura, \{Henry I.\}",

note = "Funding Information: This work was supported in part by U.S. Public Health Service Grants AM-21085 (V.J.H.), HL-30956 (H.I.Y.), and MH-27257 (H.I.Y.). H.I.Y. is the recipient of a Research Scientist Developmnent Award (MH-00095) from the",

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T1 - Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors

AU - Gulya, Karoly

AU - Pelton, John T.

AU - Hruby, Victor J.

AU - Yamamura, Henry I.

N1 - Funding Information: This work was supported in part by U.S. Public Health Service Grants AM-21085 (V.J.H.), HL-30956 (H.I.Y.), and MH-27257 (H.I.Y.). H.I.Y. is the recipient of a Research Scientist Developmnent Award (MH-00095) from the

PY - 1986/6/16

Y1 - 1986/6/16

N2 - A series of cyclic conformationally restricted penicillamine containing somatostatin octapeptide analogues have been prepared by standard solid phase synthetic techniques and tested for their ability to inhibit specific [125I]CGP 23,996 (des-Ala1-,Gly2-[desamino-Cys3Tyr11]-dicarba3,14- somatostatin), [3H]naloxone or [3H]DPDPE ([D-Pen2-D-Pen5]enkephalin) binding in rat brain membrane preparations. We now report structure-activity relationship studies with the syntheis of our most potent and selective mu opioid receptor compound DPheCysTyrDTrpOrnThrPenThrNH2, which we refer to as Cys2Tyr3Orn5Pen7-amide. While this octapeptide exhibited high affinity (IC50 = 2.80 nM) for an apparently single population of binding sites (nH = 0.89 ± 0.1) and exceptional selectivity for mu opioid receptos with an IC51(DPDPE)/IC50 (naloxone) ratio of 4,829, it also displayed very low affinity for somatostatin receptors (IC50 = 22,700 nM). Thus, Cys2Tyr3Orn5 Pen7-amide may be the ligand of choice for further characterization of mu opioid receptors and for examining the physiological role of this class of receptors.

AB - A series of cyclic conformationally restricted penicillamine containing somatostatin octapeptide analogues have been prepared by standard solid phase synthetic techniques and tested for their ability to inhibit specific [125I]CGP 23,996 (des-Ala1-,Gly2-[desamino-Cys3Tyr11]-dicarba3,14- somatostatin), [3H]naloxone or [3H]DPDPE ([D-Pen2-D-Pen5]enkephalin) binding in rat brain membrane preparations. We now report structure-activity relationship studies with the syntheis of our most potent and selective mu opioid receptor compound DPheCysTyrDTrpOrnThrPenThrNH2, which we refer to as Cys2Tyr3Orn5Pen7-amide. While this octapeptide exhibited high affinity (IC50 = 2.80 nM) for an apparently single population of binding sites (nH = 0.89 ± 0.1) and exceptional selectivity for mu opioid receptos with an IC51(DPDPE)/IC50 (naloxone) ratio of 4,829, it also displayed very low affinity for somatostatin receptors (IC50 = 22,700 nM). Thus, Cys2Tyr3Orn5 Pen7-amide may be the ligand of choice for further characterization of mu opioid receptors and for examining the physiological role of this class of receptors.

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Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors

Abstract

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