title: Selective effects of [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 and [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 (O-t-butyl), two new enkephalin analogues, on neurotransmitter release and adenylate cyclase in rat brain slices.
abstract: The selectivity and potency of two new enkephalin-derived delta-opioid receptor agonists, DSTBULET ([D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6) and BUBU ([D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6(O-t-butyl] were determined with functional tests in vitro of mu-, delta- and kappa-opioid receptor activation in the rat brain. Both peptides concentration dependently (1 nM-1 microM) inhibited the release of radiolabeled acetylcholine (ACh) from striatal slices (pD2 7.6-7.9), an effect exclusively mediated by delta-opioid receptor activation. Fentanyl isothiocyanate (FIT), an irreversible delta-antagonist, completely blocked the inhibitory effects of DSTBULET and BUBU. Up to a concentration of 1 microM, the peptides did not affect striatal [3H]dopamine (DA) release nor cortical [3H]noradrenaline (NA) release, processes which are known to be inhibited by opioids activating kappa and mu-receptors, respectively. Furthermore, both DSTBULET and BUBU caused a strong inhibition (pD2 8.2-8.3) of D-1 dopamine receptor-stimulated cyclic AMP efflux from striatal slices, an effect known to be mediated by mu- and/or delta-opioid receptor activation. However, the peptides were without effect when D-1 and D-2 dopamine receptors were stimulated simultaneously, a situation in which only mu-agonists are able to inhibit the resulting cAMP efflux. In conclusion, DSTBULET and BUBU appear to display a high selectivity and potency toward functional delta-opioid receptors in the brain.
authors.affiliation: Department of Pharmacology, Free University, Medical Faculty, Amsterdam, The Netherlands.
authors.forename: T J
authors.initials: TJ
authors.lastname: De Vries
authors.forename: A N
authors.initials: AN
authors.lastname: Schoffelmeer
authors.forename: P
authors.initials: P
authors.lastname: Delay-Goyet
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
authors.forename: A H
authors.initials: AH
authors.lastname: Mulder
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D004745:Enkephalins / Q000494:pharmacology*; D005283:Fentanyl / Q000031:analogs & derivatives / Q000494:pharmacology; D017879:Isothiocyanates; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000477:Alkylating Agents; D004745:Enkephalins; D017879:Isothiocyanates; D018377:Neurotransmitter Agents; D009842:Oligopeptides; C054868:tyrosyl-seryl(O-tert-butyl)-glycyl-phenylalanyl-leucyl-threonine; C062971:tyrosyl-seryl(O-t-butyl)-glycyl-phenylalanyl-leucyl-threonine(O-t-butyl); C037091:fentanyl isothiocyanate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005283:Fentanyl; D004298:Dopamine