title: Orally active oxime derivatives of the dopaminergic prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one. Synthesis and pharmacological activity.
abstract: A series of racemic and enantiomerically pure oxime derivatives of the potential anti-Parkinson prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (1) were synthesized and pharmacologically evaluated. The oximes induced rotational behavior in the Ungerstedt rat rotation model for Parkinson's disease after oral administration. Especially the unsubstituted oxime ((-)-3) and the acetyl-oxime ((-)-10) induced a pronounced and long lasting effect. In this model, large individual differences were observed in responsiveness to treatment between rats. Though less potent than the parent prodrug, the oxime derivatives of (+/-)-1 and (-)-1 can be orally active, acting as cascade prodrugs.
authors.affiliation: Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
authors.forename: Bastiaan J
authors.initials: BJ
authors.lastname: Venhuis
authors.forename: Durk
authors.initials: D
authors.lastname: Dijkstra
authors.forename: David
authors.initials: D
authors.lastname: Wustrow
authors.forename: Len T
authors.initials: LT
authors.lastname: Meltzer
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Wise
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Johnson
authors.forename: Håkan V
authors.initials: HV
authors.lastname: Wikström
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008474:Medial Forebrain Bundle / Q000293:injuries; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology; D016627:Oxidopamine / Q000633:toxicity; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D014162:Transfection
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents; D009281:Naphthalenes; D010091:Oximes; D011355:Prodrugs; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D016627:Oxidopamine