title: 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors.
abstract: Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.
authors.affiliation: GlaxoSmithKline Research and Development, 5 Moore Drive, , Research Triangle Park, North Carolina 27709, USA. michael.j.bishop@gsk.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bishop
authors.forename: Dulce M
authors.initials: DM
authors.lastname: Garrido
authors.forename: G Evan
authors.initials: GE
authors.lastname: Boswell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Collins
authors.forename: Philip A
authors.initials: PA
authors.lastname: Harris
authors.forename: Robert W
authors.initials: RW
authors.lastname: McNutt
authors.forename: Scott J
authors.initials: SJ
authors.lastname: O'Neill
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.forename: Kwen-Jen
authors.initials: KJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C471872:3-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide; D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu