title: Identification and functional separation of retinoic acid receptor neutral antagonists and inverse agonists.
abstract: Inverse agonists are ligands that are capable of repressing basal receptor activity in the absence of an agonist. We have designed a series of C-1-substituted acetylenic retinoids that exhibit potent antagonism of retinoic acid receptor (RAR)-mediated transactivation. Comparison of these related retinoid antagonists for their ability to repress basal RAR transcriptional activity demonstrates that the identity of the C-1 substituent differentiates these ligands into two groups: RAR inverse agonists and neutral antagonists. We show that treatment of cultured human keratinocytes with a RAR inverse agonist, but not a RAR neutral antagonist, leads to the repression of the serum-induced differentiation marker MRP-8. While RAR-selective agonists also repress expression of MRP-8, cotreatment with a RAR inverse agonist and a RAR agonist results in a mutual repression of their individual inhibitory activities, indicating the distinct modes of action of these two disparate retinoids in modulating MRP-8 expression. Our data indicate that RARs, like beta2-adrenoreceptors, are sensitive to inverse agonists and that this new class of retinoids will provide insight into the molecular mechanisms of RAR function in skin and other responsive tissues.
authors.affiliation: Department of Biology, Retinoid Research, Allergan Pharmaceuticals, Irvine, California 92715, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Klein
authors.forename: M E
authors.initials: ME
authors.lastname: Pino
authors.forename: A T
authors.initials: AT
authors.lastname: Johnson
authors.forename: P J
authors.initials: PJ
authors.lastname: Davies
authors.forename: S
authors.initials: S
authors.lastname: Nagpal
authors.forename: S M
authors.initials: SM
authors.lastname: Thacher
authors.forename: G
authors.initials: G
authors.lastname: Krasinski
authors.forename: R A
authors.initials: RA
authors.lastname: Chandraratna
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism; D001667:Binding, Competitive; D002135:Calcium-Binding Proteins / Q000378:metabolism; D040501:Calgranulin A; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D009281:Naphthalenes; D011943:Receptors, Adrenergic, beta; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C096920:AGN 193109