Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor

Thuy Nguyen, Jun Xu Li, Brian F. Thomas, Jenny L. Wiley, Terry P. Kenakin, Yanan Zhang

Research output: Contribution to journalReview article

  • 12 Citations

Abstract

The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details the complex pharmacological profiles of these allosteric modulators, their structure–activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators. The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.

LanguageEnglish (US)
Pages441-474
Number of pages34
JournalMedicinal Research Reviews
Volume37
Issue number3
DOIs
StatePublished - May 1 2017

Fingerprint

Cannabinoid Receptor CB1
Pharmacology
Allosteric Site
Ligands
Biological Phenomena
Endocannabinoids
Cannabinoids
Structure-Activity Relationship
G-Protein-Coupled Receptors
Nervous System Diseases
Therapeutics

Keywords

  • allosteric modulation
  • CB1 receptor
  • negative allosteric modulator (NAM)
  • positive allosteric modulator (PAM)
  • structure–activity relationship (SAR)

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Allosteric Modulation : An Alternate Approach Targeting the Cannabinoid CB1 Receptor. / Nguyen, Thuy; Li, Jun Xu; Thomas, Brian F.; Wiley, Jenny L.; Kenakin, Terry P.; Zhang, Yanan.

In: Medicinal Research Reviews, Vol. 37, No. 3, 01.05.2017, p. 441-474.

Research output: Contribution to journalReview article

Nguyen, Thuy ; Li, Jun Xu ; Thomas, Brian F. ; Wiley, Jenny L. ; Kenakin, Terry P. ; Zhang, Yanan. / Allosteric Modulation : An Alternate Approach Targeting the Cannabinoid CB1 Receptor. In: Medicinal Research Reviews. 2017 ; Vol. 37, No. 3. pp. 441-474.
@article{97c7336641d3461c9c9f7f198bb7adc3,
title = "Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor",
abstract = "The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details the complex pharmacological profiles of these allosteric modulators, their structure–activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators. The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.",
keywords = "allosteric modulation, CB1 receptor, negative allosteric modulator (NAM), positive allosteric modulator (PAM), structure–activity relationship (SAR)",
author = "Thuy Nguyen and Li, {Jun Xu} and Thomas, {Brian F.} and Wiley, {Jenny L.} and Kenakin, {Terry P.} and Yanan Zhang",
year = "2017",
month = "5",
day = "1",
doi = "10.1002/med.21418",
language = "English (US)",
volume = "37",
pages = "441--474",
journal = "Medicinal Research Reviews",
issn = "0198-6325",
publisher = "John Wiley and Sons Inc.",
number = "3",

}

TY - JOUR

T1 - Allosteric Modulation

T2 - Medicinal Research Reviews

AU - Nguyen, Thuy

AU - Li, Jun Xu

AU - Thomas, Brian F.

AU - Wiley, Jenny L.

AU - Kenakin, Terry P.

AU - Zhang, Yanan

PY - 2017/5/1

Y1 - 2017/5/1

N2 - The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details the complex pharmacological profiles of these allosteric modulators, their structure–activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators. The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.

AB - The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details the complex pharmacological profiles of these allosteric modulators, their structure–activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators. The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.

KW - allosteric modulation

KW - CB1 receptor

KW - negative allosteric modulator (NAM)

KW - positive allosteric modulator (PAM)

KW - structure–activity relationship (SAR)

UR - http://www.scopus.com/inward/record.url?scp=85005914723&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85005914723&partnerID=8YFLogxK

U2 - 10.1002/med.21418

DO - 10.1002/med.21418

M3 - Review article

VL - 37

SP - 441

EP - 474

JO - Medicinal Research Reviews

JF - Medicinal Research Reviews

SN - 0198-6325

IS - 3

ER -