Sar studies of piperidine-based analogues of cocaine. Part 3: oxadiazoles.
The synthesis of novel 4beta-aryl-1-methyl-3alpha-(3-substituted-1,2,4-oxadiazol-5-yl)piperidines, bioisosteres of ester (+)-1, is described. The synthesized oxadiazoles were evaluated for their affinity to the DAT and their ability to inhibit monoamine reuptake at the DAT, NET, and 5HTT. The results show that affinity to the DAT and ability to inhibit the reuptake at the DAT, NET, and 5HTT is a function of the size of the substituent in the oxadiazole ring. (+)-(3R,4S)-4beta-(4-Chlorophenyl)-1-methyl-3alpha-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine [(+)-2a], which is structurally and pharmacologically most similar to the ester (+)-1 in this series, showed at least a 2-fold longer duration of action when compared to ester (+)-1.
Petukhov
P A
PA
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road, N.W., Washington, DC 20007, USA.
Zhang
M
M
Johnson
K J
KJ
Tella
S R
SR
Kozikowski
A P
AP
D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010069:Oxadiazoles; D010880:Piperidines; C032727:piperidine; D003042:Cocaine