title: Agonist Activity of the delta-antagonists TIPP and TIPP-psi in cellular models expressing endogenous or transfected delta-opioid receptors.
abstract: A new class of highly selective delta-opioid receptor antagonists has been recently developed, termed the TIP(P) peptides. Two prototypical compounds in this class are TIPP (H-Tyr-Tic-Phe-Phe-OH) and a derivative, TIPP-psi (H-Tyr-Tic[CH2NH]-Phe-Phe-OH). Surprisingly, both TIPP and TIPP-psi demonstrated inhibition of adenylyl cyclase activity in GH3 cells transfected with delta-opioid receptors (GH3DORT), an effect normally observed by agonists. The agonist activity was delta-selective, because no inhibition occurred in wild-type GH3 or GH3MOR (mu-opioid receptor) cells. Both TIPP and TIPP-psi exhibited concentration-dependent inhibition of adenylyl cyclase activity; however, TIPP-psi was found to be less potent (IC50 = 3.97 versus 0.162 nM) and less efficacious (I(max) = 50% versus 70%) than TIPP. Pretreatment of cells with pertussis toxin attenuated the inhibition of maximally effective concentrations of TIPP and TIPP-psi, indicating the involvement of G(i)alpha/G(o)alpha G-proteins. Other delta-antagonists, naltriben, naloxone, and ICI 174864, attenuated the inhibition of adenylyl cyclase activity mediated by TIPP. Coadministration of TIPP with the selective delta-agonist [D-Pen2,5]enkephalin resulted in an additive interaction. Both TIPP and TIPP-psi exhibited significant inhibition of adenylyl cyclase activity in different GH3DORT clones expressing a 28-fold range of delta-opioid receptor densities, and in cell lines expressing endogenous (i.e., N1E115 and NG108-15) and transfected (i.e., Chinese hamster ovary-DOR and human embryonic kidney-DOR) delta-opioid receptors, with densities ranging from 0.12 to 6.67 pmol/mg. These results suggest that compounds previously thought to be purely delta-opioid receptor antagonists also demonstrate agonist activity in several in vitro models.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Martin
authors.forename: M T
authors.initials: MT
authors.lastname: Terruso
authors.forename: P L
authors.initials: PL
authors.lastname: Prather
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D004174:Diprenorphine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D006801:Humans; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000187:drug effects* / Q000378:metabolism; D044005:Tetrahydroisoquinolines
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C092721:tyrosyl-tetrahydroisoquinolinecarbonyl-psi(methylamino)phenylalanyl-phenylalanine; C082263:tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine; D004174:Diprenorphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D000242:Cyclic AMP; D000262:Adenylyl Cyclases