MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hurst, D. P.
Right arrow Articles by Reggio, P. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hurst, D. P.
Right arrow Articles by Reggio, P. H.

Vol. 62, Issue 6, 1274-1287, December 2002

N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) Interaction with LYS 3.28(192) Is Crucial for Its Inverse Agonism at the Cannabinoid CB1 Receptor

Dow P. Hurst, Diane L. Lynch, Judy Barnett-Norris, Stephen M. Hyatt, Herbert H. Seltzman, Miao Zhong, Zhao-Hui Song, Jingjiang Nie, Deborah Lewis, and Patricia H. Reggio

Department of Chemistry, Kennesaw State University, Kennesaw, Georgia (D.P.H., D.L.L., J.B.-N., P.H.R.); RTI International, Research Triangle Park, North Carolina (S.M.H., H.H.S.); Pharmacology and Toxicology Department, University of Louisville, Louisville, Kentucky (M.Z., Z.-H.S.); and Pharmacology and Toxicology Department, Medical College of Georgia, Augusta, Georgia (J.N., D.L.)

In superior cervical ganglion neurons, N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) competitively antagonizes the Ca2+ current effect of the cannabinoid (CB) agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), and behaves as an inverse agonist by producing opposite current effects when applied alone. In contrast, in neurons expressing CB1 with a Kright-arrowA mutation at residue 3.28(192) (i.e., K3.28A), SR141716A competitively antagonizes the effects of WIN55212-2, but behaves as a neutral antagonist by producing no current effects itself. Receptor modeling studies suggested that in the CB1 inactive (R) state, SR1417A16A stabilizes transmembrane helix 6 in its inactive conformation via aromatic stacking with F3.36/W6.48. In this binding site, SR141716A would exhibit higher affinity for CB1 R due to a hydrogen bond between the SR141716A C3 substituent and K3.28(192), a residue available to SR141716A only in R. To test this hypothesis, a "mutant thermodynamic cycle" was constructed that combined the evaluation of SR141716A affinity at WT CB1 and K3.28A with an evaluation of the wild-type CB1 and K3.28A affinities of an SR141716A analog, 5-(4-chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole (VCHSR), that lacks hydrogen bonding potential at C3. Binding affinities suggested that K3.28 is involved in a strong interaction with SR141716A in WT CB1, but does not interact with VCHSR. Thermodynamic cycle calculations indicated that a direct interaction occurs between the C3 substituent of SR141716A and K3.28 in WT CB1. Consistent with these results, VCHSR acted as a neutral antagonist at WT CB1. These results support the hypothesis that hydrogen bonding of the SR141716A C3 substituent with K3.28 is responsible for its higher affinity for the inactive R state, leading to its inverse agonism.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
J. L. Niehaus, Y. Liu, K. T. Wallis, M. Egertova, S. G. Bhartur, S. Mukhopadhyay, S. Shi, H. He, D. E. Selley, A. C. Howlett, et al.
CB1 Cannabinoid Receptor Activity Is Modulated by the Cannabinoid Receptor Interacting Protein CRIP 1a
Mol. Pharmacol., December 1, 2007; 72(6): 1557 - 1566.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. Kapur, D. P. Hurst, D. Fleischer, R. Whitnell, G. A. Thakur, A. Makriyannis, P. H. Reggio, and M. E. Abood
Mutation Studies of Ser7.39 and Ser2.60 in the Human CB1 Cannabinoid Receptor: Evidence for a Serine-Induced Bend in CB1 Transmembrane Helix 7
Mol. Pharmacol., June 1, 2007; 71(6): 1512 - 1524.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
K. Chen, A. Neu, A. L. Howard, C. Foldy, J. Echegoyen, L. Hilgenberg, M. Smith, K. Mackie, and I. Soltesz
Prevention of Plasticity of Endocannabinoid Signaling Inhibits Persistent Limbic Hyperexcitability Caused by Developmental Seizures
J. Neurosci., January 3, 2007; 27(1): 46 - 58.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
D. Sarnataro, S. Pisanti, A. Santoro, P. Gazzerro, A. M. Malfitano, C. Laezza, and M. Bifulco
The Cannabinoid CB1 Receptor Antagonist Rimonabant (SR141716) Inhibits Human Breast Cancer Cell Proliferation through a Lipid Raft-Mediated Mechanism
Mol. Pharmacol., October 1, 2006; 70(4): 1298 - 1306.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. P. Picone, A. D. Khanolkar, W. Xu, L. A. Ayotte, G. A. Thakur, D. P. Hurst, M. E. Abood, P. H. Reggio, D. J. Fournier, and A. Makriyannis
(-)-7'-Isothiocyanato-11-hydroxy-1',1'-dimethylheptylhexahydrocannabinol (AM841), a High-Affinity Electrophilic Ligand, Interacts Covalently with a Cysteine in Helix Six and Activates the CB1 Cannabinoid Receptor
Mol. Pharmacol., December 1, 2005; 68(6): 1623 - 1635.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. Zhang, D. P. Hurst, J. Barnett-Norris, P. H. Reggio, and Z.-H. Song
Cysteine 2.59(89) in the Second Transmembrane Domain of Human CB2 Receptor Is Accessible within the Ligand Binding Crevice: Evidence for Possible CB2 Deviation from a Rhodopsin Template
Mol. Pharmacol., July 1, 2005; 68(1): 69 - 83.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. D. McAllister, D. P. Hurst, J. Barnett-Norris, D. Lynch, P. H. Reggio, and M. E. Abood
Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches: THE IMPORTANCE OF THE F3.36(201)/W6.48(357) INTERACTION IN CANNABINOID CB1 RECEPTOR ACTIVATION
J. Biol. Chem., November 12, 2004; 279(46): 48024 - 48037.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics