Novel cyclic biphalin analogue with improved antinociceptive properties

Adriano Mollica; Alfonso Carotenuto; Ettore Novellino; Antonio Limatola; Roberto Costante; Francesco Pinnen; Azzurra Stefanucci; Stefano Pieretti; Anna Borsodi; Reza Samavati; Ferenc Zador; Sándor Benyhe; Peg Davis; Frank Porreca; Victor J. Hruby

doi:10.1021/ml500241n

Novel cyclic biphalin analogue with improved antinociceptive properties

Adriano Mollica
, Alfonso Carotenuto
, Ettore Novellino
, Antonio Limatola
, Roberto Costante
, Francesco Pinnen
, Azzurra Stefanucci
, Stefano Pieretti
, Anna Borsodi
, Reza Samavati
, Ferenc Zador
, Sándor Benyhe
, Peg Davis
, Frank Porreca
, Victor J. Hruby

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

38 Scopus citations

Abstract

Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2′ of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (K_i^δ = 5.2 nM; K_i^μ = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties.

Original language	English (US)
Pages (from-to)	1032-1036
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	9
DOIs	https://doi.org/10.1021/ml500241n
State	Published - Sep 11 2014

Keywords

Analgesics
biphalin
cyclic analogues
dimeric opioid peptides

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml500241n

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title = "Novel cyclic biphalin analogue with improved antinociceptive properties",

abstract = "Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2′ of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (Kiδ = 5.2 nM; Kiμ = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties.",

keywords = "Analgesics, biphalin, cyclic analogues, dimeric opioid peptides",

author = "Adriano Mollica and Alfonso Carotenuto and Ettore Novellino and Antonio Limatola and Roberto Costante and Francesco Pinnen and Azzurra Stefanucci and Stefano Pieretti and Anna Borsodi and Reza Samavati and Ferenc Zador and S{\'a}ndor Benyhe and Peg Davis and Frank Porreca and Hruby, \{Victor J.\}",

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day = "11",

doi = "10.1021/ml500241n",

language = "English (US)",

volume = "5",

pages = "1032--1036",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

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TY - JOUR

T1 - Novel cyclic biphalin analogue with improved antinociceptive properties

AU - Mollica, Adriano

AU - Carotenuto, Alfonso

AU - Novellino, Ettore

AU - Limatola, Antonio

AU - Costante, Roberto

AU - Pinnen, Francesco

AU - Stefanucci, Azzurra

AU - Pieretti, Stefano

AU - Borsodi, Anna

AU - Samavati, Reza

AU - Zador, Ferenc

AU - Benyhe, Sándor

AU - Davis, Peg

AU - Porreca, Frank

AU - Hruby, Victor J.

PY - 2014/9/11

Y1 - 2014/9/11

N2 - Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2′ of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (Kiδ = 5.2 nM; Kiμ = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties.

AB - Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2′ of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (Kiδ = 5.2 nM; Kiμ = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties.

KW - Analgesics

KW - biphalin

KW - cyclic analogues

KW - dimeric opioid peptides

UR - https://www.scopus.com/pages/publications/84907501785

UR - https://www.scopus.com/pages/publications/84907501785#tab=citedBy

U2 - 10.1021/ml500241n

DO - 10.1021/ml500241n

M3 - Article

AN - SCOPUS:84907501785

SN - 1948-5875

VL - 5

SP - 1032

EP - 1036

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 9

ER -

Novel cyclic biphalin analogue with improved antinociceptive properties

Abstract

Keywords

ASJC Scopus subject areas

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