Separation of binding affinity and intrinsic activity of the potent μ-opioid 14-methoxymetopon Journal Article
| Authors: | Mahurter, L.; Garceau, C.; Marino, J.; Schmidhammer, H.; Tóth, G.; Pasternak, G. W. |
| Article Title: | Separation of binding affinity and intrinsic activity of the potent μ-opioid 14-methoxymetopon |
| Abstract: | Receptor binding studies of 5,14-O-dimethyloxymorphone (14-methoxymetopon) in brain membranes have established its high affinity for μ-binding sites, but its analgesic potency far exceeds the modest increase in binding affinity relative to other opioids. The current study has established the selectivity of [3H]14-methoxymetopon for μ sites in calf striatal membranes and for a number of full-length splice variants of the cloned murine μ-opioid receptor 1 (mMOR-1) in transfected cell lines. The binding affinity of [ 3H]14-methoxymetopon for the variants expressed in Chinese hamster ovary cells was quite high, with KD values around 0.2 nM for all of the variants with the exception of mMOR-1F (KD of 1.2 nM). The affinity for most of the expressed variants was greater than that seen in the brain membranes (KD of 0.99 nM). Functionally, in guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays with the MOR-1 variants, 14-methoxymetopon and the μ-opioid peptide [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) showed similar efficacies, as determined by maximal stimulation, but 14-methoxymetopon was up to 65-fold more potent than DAMGO. The greatest difference was seen with mMOR-1E and the least with mMOR-1C, which displayed only a 10-fold difference. These potency differences in the stimulation of [35S]GTPγS binding far exceeded the differences in binding affinity. The differences between 14-methoxymetopon and DAMGO remained after normalizing the potency shifts based upon receptor binding affinities and varied from 1.2-fold with mMOR-1C to 21-fold for mMOR-1 and 42-fold with mMOR-1F. Thus, 14-methoxymetopon is a potent agonist against all of the mMOR-1 splice variants, but its potency ranged widely despite similar binding affinities for most of the variants and may give insight into its unusual pharmacological profile. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics. |
| Keywords: | unclassified drug; drug activity; nonhuman; binding affinity; animals; animal tissue; cell line; drug potency; molecular cloning; binding site; cattle; receptor affinity; guanosine triphosphate; receptors, opioid, mu; corpus striatum; opiate receptor; enkephalin, ala(2)-mephe(4)-gly(5)-; guanosine 5'-o-(3-thiotriphosphate); striate cortex; binding assay; opiate peptide; enkephalin[2 dextro alanine 4 methylphenylalanine 5 glycine]; 14 methoxymetopon; opiate agonist; brain membrane; morphine derivatives |
| Journal Title: | Journal of Pharmacology and Experimental Therapeutics |
| Volume: | 319 |
| Issue: | 1 |
| ISSN: | 0022-3565 |
| Publisher: | American Society for Pharmacology and Experimental Therapeutics |
| Date Published: | 2006-10-01 |
| Start Page: | 247 |
| End Page: | 253 |
| Language: | English |
| DOI: | 10.1124/jpet.106.105395 |
| PUBMED: | 16801454 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 4 June 2012" - "CODEN: JPETA" - "Source: Scopus" |
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