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.
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.
Venhuis
Bastiaan J
BJ
Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
Dijkstra
Durk
D
Wustrow
David
D
Meltzer
Len T
LT
Wise
Lawrence D
LD
Johnson
Stephen J
SJ
Wikström
Håkan V
HV
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
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