In order to develop systemically-active opioid peptides, the delta-selective, opioid pentapeptide [D-Pen2,D-Pen5]-enkephalin (DPDPE) was modified by esterification and by substitution of 2',6'-dimethyltyrosine for tyrosine to yield 4. Compound 4 was on the order of 8- and 800-fold more active than DPDPE in both delta and mu opioid radioligand binding assays, respectively, in rat neural membrane suspensions. Compound 4 was considerably more potent than DPDPE at inhibiting contractions of electrically-stimulated mouse vas deferens in vitro, and this effect was very sensitive to naltrindole, a delta-selective opioid antagonist. These observations can be taken as indication that 4 exerts its effects through delta opioid receptors. This interpretation is supported by the finding that the EC50 value of 4 derived in the smooth muscle assay is very similar to that derived in NG108-15 neuroblastoma cells, a preparation devoid of mu receptors. Unlike DPDPE, 4 exhibited significant, naloxone-sensitive, antinociceptive activity when administered systemically, as measured by inhibition of phenylbenzquinone-induced stretching in mice (ED50 = 2.1 mg/kg). Compound 4 also displayed significant antinociceptive activity following systemic administration as measured by its action in mice to increase latencies for tail withdrawal from radiant heat (ED50 = 50 mg/kg). Compound 4 did not produce morphine-like discriminative stimulus effects in rats trained to discriminate 3.0 mg/kg morphine from vehicle at doses ranging from 30 to 120 mg/kg. This observation can be interpreted as indication that within this dosage range there is an absence of morphine-like subjective effects. Physical dependence, however, could be induced in mice at higher doses of 4 under a progressively-graded, 4-day dose regimen. Congeners of 4 with amide bond surrogates for the Gly-Phe amide bond (oxymethylene, trans-double bond, and bismethylene isosteres) in the cyclic core of DPDPE were prepared in an attempt to increase the antinociceptive activity of 4. While some of the congeners were active in the in vitro assays, they did not display significant antinociceptive activity following systemic administration. The preparation of all the compounds was accomplished by solution-phase methods. The mechanisms which might underlie the biological and systemic activity of 4 are discussed.
Gavestinel [GV150526A; ( E)-3[(phenylcarbamoil)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt] is a selective antagonist at the strychnine-insensitive glycine site of the -methyl-D-aspartate (NMDA) receptor. It was tested for its ability to substitute for phencyclidine (PCP) in rats and rhesus monkeys trained to discriminate PCP from saline, under a two-lever fixed-ratio (FR) food reinforcement schedule, and for its ability to maintain responding in rhesus monkeys trained to self-administer PCP under a FR reinforcement schedule. No PCP-lever responding was observed after gavestinel (1-56 mg/kg i.p.) administration to rats discriminating PCP (2.0 mg/kg i.p.) from saline. The highest dose of gavestinel (100 mg/kg i.p.) tested eliminated responding. Likewise, no PCP-lever responding was observed after gavestinel (1-30 mg/kg s.c.) administration to rhesus monkeys discriminating PCP (0.08 or 0.1 mg/kg i.m.) from saline; the highest dose of gavestinel (30 mg/kg s.c.) tested reduced response rates to approximately 50% of those observed after its vehicle ( -cyclodextrin in 0.9% saline). Gavestinel (0.1-1 mg/kg per i.v. infusion) was not self-administered by rhesus monkeys that reliably self-administered PCP (0.0056 or 0.01 mg/kg per i.v. infusion). Infusion rates at the highest dose were typically lower than those for vehicle or saline, suggesting behavioral activity. Together, these results suggest that at behaviorally active doses gavestinel is not PCP-like and is likely to have low abuse liability.
Mu opioid receptor agonists such as morphine stimulate the release of dopamine (DA) in various brain regions. These increases in DA are thought to be involved in some of the behavioral effects of mu agonists. The present study was designed to examine the modulatory actions of two D2/3 antagonists (nafadotride and eticlopride), the D2/3 partial agonist BP897, the D1/2 antagonist flupenthixol, and the D1 antagonist SCH23390 on the discriminative stimulus effects of the mu partial agonist nalbuphine and the higher-efficacy mu agonists heroin, methadone and morphine, in rats trained to discriminate heroin from water. Both nafadotride and eticlopride attenuated the effects of the mu agonists, whereas BP897 was effective against nalbuphine and partially effective against morphine. Flupenthixol attenuated the heroin-like discriminative stimulus effects of heroin and morphine, although not as completely as nafadotride or eticlopride. SCH23390 was least effective and produced little attenuation. These results demonstrate that the discriminative stimulus effects of mu agonists in rats are more readily attenuated by drugs that block D2-like, rather than D1-like, receptors.
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