PubMed · 6514647
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R G Twycross. 1984. Analgesics.. https://doi.org/10.1136/pgmj.60.710.876
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The development of dual inhibitors of the two zinc metallopeptidases, neprilysin (neutral endopeptidase) and aminopeptidase N involved in the inactivation of the opioid peptides, enkephalins, represents an attractive physiological approach in the search for new analgesics devoid of the major drawbacks of morphine. Phosphinic compounds, corresponding to the general formula H(3)N(+)-CH(R(1))-P(O)(OH)-CH(2)-CH(R(2))-CONH-CH(R(3))-COO(-), able to act as transition-state analogues and to fit the S(1), S(1)', and S(2)' subsites of both enzymes were designed. Selection of the R(1), R(2), and R(3) residues for optimal recognition of these enzymes led to the first dual competitive inhibitors with K(i) values in the nanomolar range for neprilysin and aminopeptidase N. These compounds induce potent analgesic responses after intracerebroventricular or intravenous administrations in mice (hot plate test), and several of them were shown to be, at least, 10 times more potent than the previously described dual inhibitors.
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The present study was undertaken to assess the effects of intracerebroventricular (i.c.v.) luzindole (a selective MT(2) melatonin receptor antagonist) and prazosin (a selective MT(3) melatonin receptor antagonist) on melatonin-induced antinociception, so as to clarify which of melatonin receptor subtypes within the central nervous system (CNS) was mediating antinociception. The pain threshold of rats was measured by the hot water (50 degrees C) tail-flick test. It was found that intraperitoneal (i.p.) melatonin (30, 60, 120 mg/kg) resulted in a dose-dependent antinociception. Luzindole (50, 100 microgram) administered intracerebroventricularly antagonized significantly the antinociceptive effect induced by i.p. melatonin (120 mg/kg), whereas prazosin (50 microgram) did not. Neither luzindole (100 microgram, i.c.v.) nor prazosin (50 microgram, i.c.v.) affected the nociceptive threshold when given alone. The results suggest that melatonin-induced antinociception is mediated through the MT(2) melatonin receptor subtype within the CNS.