Novel 3-aminomethyl- and 4-aminopiperidine analogues of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazines: synthesis and evaluation as dopamine transporter ligands.
We have undertaken a program to develop cocaine antagonists based on the premise that such compounds should block cocaine binding but permit reuptake of dopamine at the dopamine transporter (DAT). To evaluate the structural features of potential cocaine antagonists, 3-aminomethylpiperidine and 4-aminopiperidine moieties were incorporated at the central bridge region (piperazine ring) of GBR 12935. The compounds were assayed as inhibitors of [(125)I]RTI-55 binding at the DAT and monoamine transport. The results indicated that most of the new compounds preferentially inhibited norepinephrine reuptake by its transporter (NET) but in some cases retained binding selectivity for the DAT. In general, the binding selectivity and potency of [(3)H]NE reuptake inhibition were very sensitive to modifications of the central bridge diamine moiety (position of two basic nitrogen atoms). Compound 6 exhibited the highest ratio (14-fold) of DA reuptake inhibition to RTI-55 binding inhibition at the DAT; however, in an in vitro assay of cocaine antagonism, this compound failed to reduce inhibition of [(3)H]DA uptake by cocaine. These results demonstrated that separation of biological activities into the binding and reuptake inhibition can be achieved by alterations in the internal diamine component of GBR 12935, but additional modifications are necessary before these agents constitute lead compounds for development as cocaine antagonists.
Choi
S W
SW
Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Elmaleh
D R
DR
Hanson
R N
RN
Fischman
A J
AJ
D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493214:SLC6A3 protein, human