Functional selectivity in cannabinoid signaling.

E. V. Varga, T. Georgieva, S. Tumati, I. Alves, Z. Salamon, G. Tollin, H. I. Yamamura, William R Roeske

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.

Original languageEnglish (US)
Pages (from-to)273-284
Number of pages12
JournalCurrent Molecular Pharmacology
Volume1
Issue number3
StatePublished - Nov 2008

Fingerprint

Cannabinoid Receptor Agonists
Cannabinoids
Cannabinoid Receptors
GTP-Binding Proteins
Pharmacology
Cannabinoid Receptor CB1
Analgesia
Analgesics
Signal Transduction
Spectrum Analysis
Central Nervous System
Membranes

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Molecular Medicine

Cite this

Varga, E. V., Georgieva, T., Tumati, S., Alves, I., Salamon, Z., Tollin, G., ... Roeske, W. R. (2008). Functional selectivity in cannabinoid signaling. Current Molecular Pharmacology, 1(3), 273-284.

Functional selectivity in cannabinoid signaling. / Varga, E. V.; Georgieva, T.; Tumati, S.; Alves, I.; Salamon, Z.; Tollin, G.; Yamamura, H. I.; Roeske, William R.

In: Current Molecular Pharmacology, Vol. 1, No. 3, 11.2008, p. 273-284.

Research output: Contribution to journalArticle

Varga, EV, Georgieva, T, Tumati, S, Alves, I, Salamon, Z, Tollin, G, Yamamura, HI & Roeske, WR 2008, 'Functional selectivity in cannabinoid signaling.', Current Molecular Pharmacology, vol. 1, no. 3, pp. 273-284.
Varga EV, Georgieva T, Tumati S, Alves I, Salamon Z, Tollin G et al. Functional selectivity in cannabinoid signaling. Current Molecular Pharmacology. 2008 Nov;1(3):273-284.
Varga, E. V. ; Georgieva, T. ; Tumati, S. ; Alves, I. ; Salamon, Z. ; Tollin, G. ; Yamamura, H. I. ; Roeske, William R. / Functional selectivity in cannabinoid signaling. In: Current Molecular Pharmacology. 2008 ; Vol. 1, No. 3. pp. 273-284.
@article{b9711e22a0994dc09f0001c9105d5e04,
title = "Functional selectivity in cannabinoid signaling.",
abstract = "Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.",
author = "Varga, {E. V.} and T. Georgieva and S. Tumati and I. Alves and Z. Salamon and G. Tollin and Yamamura, {H. I.} and Roeske, {William R}",
year = "2008",
month = "11",
language = "English (US)",
volume = "1",
pages = "273--284",
journal = "Current Molecular Pharmacology",
issn = "1874-4702",
publisher = "Bentham Science Publishers",
number = "3",

}

TY - JOUR

T1 - Functional selectivity in cannabinoid signaling.

AU - Varga, E. V.

AU - Georgieva, T.

AU - Tumati, S.

AU - Alves, I.

AU - Salamon, Z.

AU - Tollin, G.

AU - Yamamura, H. I.

AU - Roeske, William R

PY - 2008/11

Y1 - 2008/11

N2 - Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.

AB - Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.

UR - http://www.scopus.com/inward/record.url?scp=77449084445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77449084445&partnerID=8YFLogxK

M3 - Article

C2 - 20021440

AN - SCOPUS:77449084445

VL - 1

SP - 273

EP - 284

JO - Current Molecular Pharmacology

JF - Current Molecular Pharmacology

SN - 1874-4702

IS - 3

ER -