International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2

R G Pertwee; A C Howlett; M E Abood; S P H Alexander; V Di Marzo; M R Elphick; P J Greasley; Harald S. Hansen; G Kunos; K Mackie; R Mechoulam; R A Ross

doi:10.1124/pr.110.003004

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2

R G Pertwee, A C Howlett, M E Abood, S P H Alexander, V Di Marzo, M R Elphick, P J Greasley, Harald S. Hansen, G Kunos, K Mackie, R Mechoulam, R A Ross

1043 Citations (Scopus)

Abstract

There are at least two types of cannabinoid receptors (CB₁ and CB₂). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ⁹-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptormorepotently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB₁, non-CB₂ established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB₁ and/or CB₂ receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB₃" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB₁, non-CB₂ pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB₃ receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB₁ receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB₁/CB₂ receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB₁, non-CB₂ cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

Original language	English
Journal	Pharmacological Reviews
Volume	62
Issue number	4
Pages (from-to)	588-631
Number of pages	44
ISSN	0031-6997
DOIs	https://doi.org/10.1124/pr.110.003004
Publication status	Published - 1 Dec 2010

Keywords

Cannabinoids
Endocannabinoids
Humans
Ligands
Phylogeny
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptors, Cannabinoid
Terminology as Topic

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10.1124/pr.110.003004

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Pertwee, R. G., Howlett, A. C., Abood, M. E., Alexander, S. P. H., Di Marzo, V., Elphick, M. R., Greasley, P. J., Hansen, H. S., Kunos, G., Mackie, K., Mechoulam, R., & Ross, R. A. (2010). International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacological Reviews, 62(4), 588-631. https://doi.org/10.1124/pr.110.003004

Pertwee, RG, Howlett, AC, Abood, ME, Alexander, SPH, Di Marzo, V, Elphick, MR, Greasley, PJ, Hansen, HS, Kunos, G, Mackie, K, Mechoulam, R & Ross, RA 2010, 'International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2', Pharmacological Reviews, vol. 62, no. 4, pp. 588-631. https://doi.org/10.1124/pr.110.003004

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abstract = "There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptormorepotently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel {"}CB3{"} cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.",

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AU - Pertwee, R G

AU - Howlett, A C

AU - Abood, M E

AU - Alexander, S P H

AU - Di Marzo, V

AU - Elphick, M R

AU - Greasley, P J

AU - Hansen, Harald S.

AU - Kunos, G

AU - Mackie, K

AU - Mechoulam, R

AU - Ross, R A

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N2 - There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptormorepotently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB3" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

AB - There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptormorepotently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB3" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

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KW - Phylogeny

KW - Receptor, Cannabinoid, CB1

KW - Receptor, Cannabinoid, CB2

KW - Receptors, Cannabinoid

KW - Terminology as Topic

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DO - 10.1124/pr.110.003004

M3 - Journal article

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SN - 0031-6997

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SP - 588

EP - 631

JO - Pharmacological Reviews

JF - Pharmacological Reviews

IS - 4

ER -

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2

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