title: Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins.
abstract: According to classical models of drug-receptor interactions, competitive antagonists share with agonists the ability to bind to a common site on the receptor molecule. However, they are different from agonists, as they cannot trigger the "stimulus" that leads to biological responses--i.e., they lack intrinsic activity. For those receptors whose signals are transduced to effector systems by GTP-binding regulatory proteins (G proteins), a mechanistic equivalent of such a stimulus is an increased ability of agonist-bound receptor to accelerate nucleotide exchange and thus GTPase activity on the G-protein molecule. Here we show that for a member of this family of receptors (delta opioid receptors in membranes of NG108-15 neuroblastoma-glioma cells), two types of competitive antagonists can be distinguished. One type has no intrinsic activity, since it neither stimulates nor inhibits the GTPase activity of G proteins and its apparent affinity for the receptor is not altered by pertussis toxin-mediated uncoupling of receptor and G protein. The second type, however, can inhibit GTPase and thus exhibits negative intrinsic activity; its affinity for receptors is increased following uncoupling from G proteins. The existence of antagonists with negative intrinsic activity may be a general feature of several classes of neurotransmitters or hormone receptors and calls for a reevaluation of biological effects produced by competitive antagonists.
authors.affiliation: Department of Neuropharmacology, Max-Planck-Institut fur Psychiatrie, Martinsried, Federal Republic of Germany.
authors.forename: T
authors.initials: T
authors.lastname: Costa
authors.forename: A
authors.initials: A
authors.lastname: Herz
mesh_terms: D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D005033:Ethylmaleimide / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005910:Glioma; D007700:Kinetics; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009447:Neuroblastoma; D037342:Pertussis Toxin; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D001575:Benzomorphans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D010566:Virulence Factors, Bordetella; C027247:MR 2266; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine; D037342:Pertussis Toxin; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D005033:Ethylmaleimide