title: Evaluation of U-50,488H analogs for neuroprotective activity in the gerbil.
abstract: U-50,488H, a kappa (kappa) opioid ligand with moderate potency at sigma (sigma) receptors, protects against mechanical and ischemia-induced injury. The purpose of this study was to evaluate the possibility that sigma-receptors may be involved in mediating the neuroprotective actions of U-50,488H. This possibility was examined by testing the potential of a series of U-50,488H analogs, which are potent sigma-ligands with minimal activity at kappa-opioid receptors, to protect against ischemia-induced neuronal damage in the gerbil. Like U-50,488H, BD-449 (20 mg/kg), the cis-diastereomer of U-50,4888H, protected against ischemia-induced neuronal damage as did BD-737 (50 and 30 mg/kg) and BD-738 (50 mg/kg). All 3 compounds interacted selectively with sigma-receptors. In contrast, BD-601 (50 mg/kg), did not protect against ischemia-induced neuronal damage, although it also interacted potently with sigma-receptors. One difference between the compounds that were neuroprotective and BD-601 is that only BD-601 produced sigma-like behavioral effects in the rat. Thus, it is possible that BD-601 may interact differently or at a different sigma-subtype than BD-449, BD-737 and BD-738 with sigma-receptors. However, these results clearly indicate that an interaction with kappa-opioid receptors is not required for anti-ischemic activity, and that sigma-receptors may play a role in neuroprotection.
authors.affiliation: CNSDR, G.D. Searle & Co., Chesterfield, MO 63198.
authors.forename: P C
authors.initials: PC
authors.lastname: Contreras
authors.forename: D M
authors.initials: DM
authors.lastname: Ragan
authors.forename: M E
authors.initials: ME
authors.lastname: Bremer
authors.forename: T H
authors.initials: TH
authors.lastname: Lanthorn
authors.forename: N M
authors.initials: NM
authors.lastname: Gray
authors.forename: S
authors.initials: S
authors.lastname: Iyengar
authors.forename: A E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: B R
authors.initials: BR
authors.lastname: de Costa
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology*; D005849:Gerbillinae; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects; D017473:Receptors, Opioid, kappa; D017480:Receptors, sigma
chemical_list: D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017480:Receptors, sigma; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer