QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.012070v1 68/4/1079    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xie, Z. Articles by Portoghese, P. S. Search for Related Content PubMed PubMed Citation Articles by Xie, Z. Articles by Portoghese, P. S.

Interaction of Bivalent Ligand KDN21 with Heterodimeric - Opioid Receptors in Human Embryonic Kidney 293 Cells

Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota

KDN21 is a bivalent ligand that contains and opioid antagonist pharmacophores linked through a 21-atom spacer. It has been reported that KDN21 bridges and receptors that are organized as heterodimers. We have shown previously that when using [³H]diprenorphine as radioligand, KDN21 displayed greatly enhanced affinity in this series for coexpressed and opioid receptors (CDK). The present study used in vitro expression systems to investigate interactions of members of the KDN series with - heterodimers through competition binding using selective ligands and the mitogen-activated protein kinase (MAPK) assay. In this regard, the use of the selective radioligands [³H]naltrindole and [³H]norbinaltorphimine (nor-BNI) in competition binding studies revealed that KDN21 has much higher affinity than other KDN members for CDK and bound to CDK more selectively relative to mixed and opioid receptors or singly expressed and opioid receptors. Other experiments revealed that the binding of naltrindole to opioid receptors could increase the binding of nor-BNI to opioid receptors and vice versa, suggesting reciprocal allosteric modulation of receptors in the heterodimer. Regarding the selectivity of KDN21 for phenotypic and opioid receptors, we investigated the effect of KDN21 on the activation of MAPKs [extracellular signal-regulated kinases 1 and 2 (ERK1/2)] by - or -selective agonists. KDN21 inhibited the activation of ERK1/2 by [D-Pen²,D-Pen⁵]-enkephalin (₁) and bremazocine (₂) but had no effect on the activation by deltorphin II (₂) and (+)-(5,7,8)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide (U69593, ₁). 7-Benzylidenenaltrexone (₁) and bremazocine (₂) significantly reduced the binding of KDN21 to CDK, whereas naltriben (₂) and U69593 produced no such change. Taken together, these data support the idea that the organization of and receptors as heterodimers gives rise to ₁ and ₂ phenotypes.

Address correspondence to: Dr. Philip S. Portoghese, 308 Harvard Street SE, Minneapolis, MN 55455. E-mail: porto001{at}maroon.tc.umn.edu

This article has been cited by other articles:

				Z. Xie and G. M. Miller {beta}-Phenylethylamine Alters Monoamine Transporter Function via Trace Amine-Associated Receptor 1: Implication for Modulatory Roles of Trace Amines in Brain J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 617 - 628. [Abstract] [Full Text] [PDF]

				Z. Xie, S. V. Westmoreland, and G. M. Miller Modulation of Monoamine Transporters by Common Biogenic Amines via Trace Amine-Associated Receptor 1 and Monoamine Autoreceptors in Human Embryonic Kidney 293 Cells and Brain Synaptosomes J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 629 - 640. [Abstract] [Full Text] [PDF]

				M. M. Lunzer and P. S. Portoghese Selectivity of {delta}- and {kappa}-Opioid Ligands Depends on the Route of Central Administration in Mice J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 166 - 171. [Abstract] [Full Text] [PDF]

				Z. Xie, S. V. Westmoreland, M. E. Bahn, G.-L. Chen, H. Yang, E. J. Vallender, W.-D. Yao, B. K. Madras, and G. M. Miller Rhesus Monkey Trace Amine-Associated Receptor 1 Signaling: Enhancement by Monoamine Transporters and Attenuation by the D2 Autoreceptor in Vitro J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 116 - 127. [Abstract] [Full Text] [PDF]

				Z. Xie and G. M. Miller Trace Amine-Associated Receptor 1 Is a Modulator of the Dopamine Transporter J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 128 - 136. [Abstract] [Full Text] [PDF]

				J.-P. Pin, R. Neubig, M. Bouvier, L. Devi, M. Filizola, J. A. Javitch, M. J. Lohse, G. Milligan, K. Palczewski, M. Parmentier, et al. International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the Recognition and Nomenclature of G Protein-Coupled Receptor Heteromultimers Pharmacol. Rev., March 1, 2007; 59(1): 5 - 13. [Abstract] [Full Text] [PDF]

				B. K. Madras, Z. Xie, Z. Lin, A. Jassen, H. Panas, L. Lynch, R. Johnson, E. Livni, T. J. Spencer, A. A. Bonab, et al. Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 561 - 569. [Abstract] [Full Text] [PDF]

				D. J. Daniels, N. R. Lenard, C. L. Etienne, P.-Y. Law, S. C. Roerig, and P. S. Portoghese Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series PNAS, December 27, 2005; 102(52): 19208 - 19213. [Abstract] [Full Text] [PDF]