Orally active analogues 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 analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (6), an enone prodrug of the mixed DA D(1)/D(2) agonist 5,6-diOH-DPAT (2), was synthesized. The pharmacological profiles of these new enones and their in vivo pharmacological activities were investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg(-1) po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronounced and long lasting pharmacological effects. The pharmacological profile of enone 12 was found to be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01). Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence of hydroxylated metabolites of the parent enones. It is speculated that such metabolites are alpha'-hydroxylated enones that may constitute the first step in the formation of the corresponding catechols.
Venhuis
Bastiaan J
BJ
Department of Medicinal Chemistry, University Centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
Dijkstra
Durk
D
Wustrow
David J
DJ
Meltzer
Leonard T
LT
Wise
Lawrence D
LD
Johnson
Stephen J
SJ
Heffner
Thomas G
TG
Wikström
Håkan V
HV
D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed
C471868:6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D008024:Ligands; D009281:Naphthalenes; D011355:Prodrugs; D015081:2-Naphthylamine