Pharmacology, biochemistry, and behavior
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Pharmacol. Biochem. Behav. · Mar 1996
3-O-acetylmorphine-6-O-sulfate: a potent, centrally acting morphine derivative.
In view of the potent analgesia exhibited by the apparent structurally dissimilar morphine-6-O-glucuronide (M6G) and morphine-6-O-sulfate (M6S) conjugates of morphine, we have examined the effect of structural modification of M6S on analgesic activity, using the tail-flick test. Changes in the M6S structure were made that would affect the lipophilicity and polarity of the molecule. Subcutaneous (sc) and intracerebroventricular (ICV) administration of equimolar doses of morphine, M6S, 3-O-acetylmorphine-6-O-sulfate (M3A6S), 3-O-benzoylmorphine-6-O-sulfate (M3B6S), and 3-O-acetyl-N-methylmorphinium-6-O-sulfate (MM3A6S) were employed. ⋯ In contrast, the nonanalgesic compounds M3B6S and MM3A6S showed weak receptor binding ability compared to morphine. These results indicate that lipophilicity alone is not a determinant of analgesic activity in these novel morphine derivatives. These modified effects of morphine by the conjugations at the 3- and 6-position, appear to be due to their altered interactions with opioid receptors.