Carbamate ester derivatives as potential prodrugs of the presynaptic dopamine autoreceptor agonist (-)-3-(3-hydroxyphenyl)-N-propylpiperidine.
Twenty derivatives bearing substituents on the phenolic function of (-)-3-(3-hydroxyphenyl)-N-propylpiperidine [(-)-3-PPP] were synthesized and tested as prodrugs. The carbamate ester derivatives were found to be the most suitable prodrugs, and especially the 4-isopropylphenylcarbamate 20 was capable of escaping the first-pass metabolism and still generating high plasma levels of the parent compound. Four hours after an oral dose of 100 mumol/kg to rats, a plasma level of 2400 nmol/L of (-)-3-PPP was detected by an HPLC method. This was 90 times the level reached after 4 h (27 nmol/L) when (-)-3-PPP itself was given orally at the same dose.
Thorberg
S O
SO
Astra Alab AB, Research & Development Laboratories, Södertälje, Sweden.
Berg
S
S
Lundström
J
J
Pettersson
B
B
Wijkström
A
A
Sanchez
D
D
Lindberg
P
P
Nilsson
J L
JL
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*; D010880:Piperidines / Q000378:metabolism*; D011355:Prodrugs / Q000097:blood / Q000138:chemical synthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013329:Structure-Activity Relationship
D002219:Carbamates; D004364:Pharmaceutical Preparations; D010880:Piperidines; D011355:Prodrugs; D011954:Receptors, Dopamine; C026539:preclamol