PubMed · 8759691
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M Robinson. 1996. First do no harm.. https://pubmed.ncbi.nlm.nih.gov/8759691/
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The present study examined whether morphine and morphine-6beta-glucuronide (M6G) analgesia on the tail-flick and jump tests differed in potency in the periaqueductal gray, the locus coeruleus or the rostral ventromedial medulla. Morphine and M6G significantly and dose-dependently elicited analgesia on both nociceptive tests from each site. Site-specific differences were observed in the potency of M6G, but not morphine analgesia on both tests. Periaqueductal gray placements displayed analgesic ED50s on the tail-flick (morphine: 2.1 microgram, M6G: 0.2 microgram) and jump (morphine: 2.2 microgram, M6G: 0.4 microgram) tests with respective potency ratios of 12.9 and 6.5. Locus coeruleus placements displayed analgesic ED50s on the tail-flick (morphine: 1.7 microgram, M6G: 0.1 microgram) and jump (morphine: 3.4 microgram, M6G: 0.2 microgram) tests with respective potency ratios of 15.9 and 15.1. Rostral ventromedial placements displayed analgesic ED50s on the tail-flick (morphine: 1.4 microgram, M6G: 0.06 microgram) and jump (morphine: 1.9 microgram M6G: 0.08 microgram) tests with potency ratios of 21.9 on both tests. The greater analgesic sensitivity of the rostral ventromedial medulla to M6G may be due to either pharmacodynamic (splice variants of the MOR-1 gene) and/or pharmacokinetic (lipid solubility) factors.
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The synthesis and biological activity of a methylamine-bridged enkephalin analogue (MABE) is presented. The key step in the synthesis of the target compound involves the ring opening of Cbz-d-serine beta-lactone with Boc-Phe-NHCH2CH2NHCH3. Further synthetic elaboration of the resulting building block yielded compound 1 (MABE, Tyr-c[(NbetaCH3)-D-A2pr-Gly-Phe-NHCH2CH2-], where A2pr is a 2,3-diaminopropionic acid residue). Utilizing a combination of NMR and molecular modeling, the structure-biological activity relationships for compound 1 were studied. Using an in vitro isolated receptor assay, MABE was found to have affinities for isolated mu delta, and kappa opioid receptors of 1.6, 2.1, and 340 nM, respectively. By an in vivo thermal escape assay, MABE was found to have an ED50 of 0.027 microg in the rat when administered intrathecally. This effect was reversed by naloxone. By comparison, DAMGO, morphine, and DPDPE were found to yield ED50 values of 0.14, 2.4, and 54 microg, respectively, in the same assay.