morphinans and 7-benzylidenenaltrexone

7-Benzylidenenaltrexone (BNTX) and most of its derivatives showed in vitro antimalarial activities against chloroquine-resistant and -sensitive

Topics: Antimalarials; Benzylidene Compounds; Humans; Morphinans; Naltrexone; Nuclear Magnetic Resonance, Biomolecular; Plasmodium falciparum; Structure-Activity Relationship

Recently, we reported that the δ opioid receptor (DOR) agonist KNT-127 produces anxiolytic-like effects in behaving rats. Here, we report on the roles of DOR subtypes ( DOR(1) and DOR(2)) play in mediating KNT-127-induced anxiolytic-like effects. Pretreatment with the DOR(2)-selective antagonist naltriben (NTB; 0.05mg/kg, s.c.) completely abolished KNT-127 (3.0mg/kg, s.c.)-induced anxiolytic-like effects in rats performing the elevated plus-maze task. By contrast, the DOR(1)-selective antagonist 7-benzylidenenaltrexone (BNTX; 0.5mg/kg, s.c.) produced no effect at a dose that completely blocked the antinociceptive effects of KNT-127. These findings were also supported by results from a light/dark test and open-field test. We clearly demonstrated that the DOR(2)-selective antagonist, but not the DOR(1)-selective antagonist, abolishes the anxiolytic-like effects of the DOR agonist KNT-127, suggesting different roles of these DOR subtypes in anxiety. We propose that DOR(2)-selective agonists would be good candidates for future development of anxiolytic drugs.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Benzylidene Compounds; Exploratory Behavior; Formaldehyde; Male; Maze Learning; Morphinans; Naltrexone; Narcotic Antagonists; Neuropsychological Tests; Nociception; Rats; Rats, Wistar; Receptors, Opioid, delta

The identification of opioid delta receptor subtypes in mouse brain led to the investigation of the nature of the opioid delta receptors in the mouse isolated vas deferens in vitro. Noncumulative concentration-effect curves were constructed for DPDPE (delta 1 agonist) and [D-Ala2, Glu4]deltorphin (delta 2 agonist) in control tissues, or in tissues which had been incubated with either [D-Ala2, Leu5, Cys6] enkephalin (DALCE) (noncompetitive delta 1 antagonist) or 5'-naltrindole isothiocyanate (5'-NTII) (noncompetitive delta 2 antagonist). Incubation of the tissues with DALCE, under either oxygenated or nonoxygenated conditions, did not alter the concentration-effect curves for either agonist. In contrast, incubation of the tissues with 5'-NTII resulted in a significant rightward displacement of the concentration-effect curves of both DPDPE and [D-Ala2, Glu4] deltorphin. Additionally, naltriben, a selective and competitive delta 2 antagonist, showed no significant difference in its ability to antagonize a fixed, submaximal concentration of either DPDPE or [D-Ala2, Glu4]deltorphin. Furthermore, there was no significant difference in the affinity of naloxone (i.e., pA2) at the receptor(s) acted upon by either DPDPE or [D-Ala2, Glu4]deltorphin. Tolerance to DPDPE or [D-Ala2, Glu4]deltorphin was produced by incubation of the tissues with these agonists; construction of the [D-Ala2, Glu4]deltorphin concentration-effect curve in DPDPE-tolerant tissues demonstrated cross-tolerance between these agonists and, conversely, construction of DPDPE concentration-effect curves in [D-Ala2, Glu4]deltorphin-tolerant tissues revealed cross-tolerance between these agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzylidene Compounds; Drug Tolerance; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; In Vitro Techniques; Isothiocyanates; Male; Mice; Mice, Inbred ICR; Morphinans; Naltrexone; Oligopeptides; Receptors, Opioid, delta; Thiocyanates; Vas Deferens