Structure-activity relationship studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: Evaluation of behavioral activity of O- and N-analogues and their binding to monoamine transporters
Ak. Dutta et al., Structure-activity relationship studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: Evaluation of behavioral activity of O- and N-analogues and their binding to monoamine transporters, J MED CHEM, 44(6), 2001, pp. 937-948
In our effort to develop a pharmacotherapy for the treatment of cocaine add
iction, we embarked on synthesizing novel molecules targeting the dopamine
transporter (DAT) molecule in the brain as DAT has been implicated strongly
in the reinforcing effect of cocaine. Our previously developed DAT-selecti
ve piperidine analogue, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, wa
s the basis for our current structure-activity relationship (SAR) studies e
xploring the significance of the contribution of the benzhydryl O- and N-at
oms in these molecules in interacting with the DAT. Thus, we replaced the b
enzhydryl O-atom with an N-atom, altered the location of the benzhydryl N-a
tom to an adjacent position, and in one other occasion converted the benzhy
dryl O-ether linkage into an oxime-type derivative. Furthermore, we also ev
aluated the important contribution of the piperidine N-atom to binding by a
ltering its pK(a) value chemically. Novel analogues were tested for potency
in inhibiting [H-3]WIN 35,428, [H-3]- citalopram, and [H-3]nisoxetine bind
ing at the DAT, serotonin transporter (SERT), and norepinepherine transport
er (NET). [H-3]DA was used to measure DA reuptake inhibition. The results i
ndicated that the benzhydryl O- and N-atoms are exchangeable for the most p
art. On the other hand, an enhanced interaction with the SEPT was observed
when the benzhydryl N-atom moved to an adjacent position (21a; DAT (IC50) =
19.7, SEPT (IC50) = 137 nM, NET (IC50) = 1111 nM). In either cases, furthe
r alkylation of the N-atom reduced the activity for the transporter. The pr
esence of a powerful electron-withdrawing cyano group in compound 5d expect
edly produced the most potent and selective ligand for the DAT (DAT (IC50)
= 3.7 nM, DAT/SERT = 615). Selected compounds were further analyzed in the
dopamine reuptake inhibition assay. Preliminary behavioral assessment of so
me of the selected compounds in mice indicated that these compounds are muc
h less stimulating when compared with cocaine at comparable doses. In drug-
discrimination studies these selected compounds incompletely generalized fr
om the cocaine stimulus in mice trained to discriminate 10 mg/kg cocaine fr
om vehicle.