Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism

Yeon Sun Lee; Michael Remesic; Cyf Ramos-Colon; Zhijun Wu; Justin Lavigne; Gabriella Molnar; Dagmara Tymecka; Aleksandra Misicka; John M. Streicher; Victor J Hruby; Frank Porreca

doi:10.3390/biomedicines9060625

Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism

Yeon Sun Lee, Michael Remesic, Cyf Ramos-Colon, Zhijun Wu, Justin Lavigne, Gabriella Molnar, Dagmara Tymecka, Aleksandra Misicka, John M. Streicher, Victor J Hruby, Frank Porreca

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

3 Scopus citations

Abstract

In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC₅₀ = 52 nM, I_max = 122% cf. IC₅₀ = 59 nM, I_max = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity.

Original language	English (US)
Article number	625
Journal	Biomedicines
Volume	9
Issue number	6
DOIs	https://doi.org/10.3390/biomedicines9060625
State	Published - Jun 2021

Keywords

Analgesic effects
Kappa receptor antagonists
Multifunctional activity
Opioid receptors
Peptidomimetics
Plasma stability
Template-based alignment modeling

ASJC Scopus subject areas

Medicine (miscellaneous)
Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.3390/biomedicines9060625

Cite this

@article{7ff7f7a4a66a488fa67b8137d27aff65,

title = "Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism",

abstract = "In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity.",

keywords = "Analgesic effects, Kappa receptor antagonists, Multifunctional activity, Opioid receptors, Peptidomimetics, Plasma stability, Template-based alignment modeling",

author = "Lee, {Yeon Sun} and Michael Remesic and Cyf Ramos-Colon and Zhijun Wu and Justin Lavigne and Gabriella Molnar and Dagmara Tymecka and Aleksandra Misicka and Streicher, {John M.} and Hruby, {Victor J} and Frank Porreca",

note = "Funding Information: Funding: This work was supported by grants from the Proof of Concept program of the University of Arizona (UA15-178) and National Institute of Health (P01DA06284 & P01DA41307). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = jun,

doi = "10.3390/biomedicines9060625",

language = "English (US)",

volume = "9",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "6",

}

TY - JOUR

T1 - Multifunctional enkephalin analogs with a new biological profile

T2 - Mor/dor agonism and kor antagonism

AU - Lee, Yeon Sun

AU - Remesic, Michael

AU - Ramos-Colon, Cyf

AU - Wu, Zhijun

AU - Lavigne, Justin

AU - Molnar, Gabriella

AU - Tymecka, Dagmara

AU - Misicka, Aleksandra

AU - Streicher, John M.

AU - Hruby, Victor J

AU - Porreca, Frank

N1 - Funding Information: Funding: This work was supported by grants from the Proof of Concept program of the University of Arizona (UA15-178) and National Institute of Health (P01DA06284 & P01DA41307). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/6

Y1 - 2021/6

N2 - In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity.

AB - In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity.

KW - Analgesic effects

KW - Kappa receptor antagonists

KW - Multifunctional activity

KW - Opioid receptors

KW - Peptidomimetics

KW - Plasma stability

KW - Template-based alignment modeling

UR - http://www.scopus.com/inward/record.url?scp=85107739057&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85107739057&partnerID=8YFLogxK

U2 - 10.3390/biomedicines9060625

DO - 10.3390/biomedicines9060625

M3 - Article

AN - SCOPUS:85107739057

VL - 9

JO - Biomedicines

JF - Biomedicines

SN - 2227-9059

IS - 6

M1 - 625

ER -

Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this