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

Abstract

In our effort to develop a pharmacotherapy for the treatment of cocaine addiction, 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-selective piperidine analogue, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, was the basis for our current structure-activity relationship (SAR) studies exploring the significance of the contribution of the benzhydryl O- and N-atoms in these molecules in interacting with the DAT. Thus, we replaced the benzhydryl O-atom with an N-atom, altered the location of the benzhydryl N-atom to an adjacent position, and in one other occasion converted the benzhydryl O-ether linkage into an oxime-type derivative. Furthermore, we also evaluated the important contribution of the piperidine N-atom to binding by altering its pK(a) value chemically. Novel analogues were tested for potency in inhibiting [3H]WIN 35,428, [3H]citalopram, and [3H]nisoxetine binding at the DAT, serotonin transporter (SERT), and norepinepherine transporter (NET). [3H]DA was used to measure DA reuptake inhibition. The results indicated that the benzhydryl O- and N-atoms are exchangeable for the most part. On the other hand, an enhanced interaction with the SERT was observed when the benzhydryl N-atom moved to an adjacent position (21a; DAT (IC(50)) = 19.7, SERT (IC(50)) = 137 nM, NET (IC(50)) = 1111 nM). In either cases, further alkylation of the N-atom reduced the activity for the transporter. The presence of a powerful electron-withdrawing cyano group in compound 5d expectedly produced the most potent and selective ligand for the DAT (DAT (IC(50)) = 3.7 nM, DAT/SERT = 615). Selected compounds were further analyzed in the dopamine reuptake inhibition assay. Preliminary behavioral assessment of some of the selected compounds in mice indicated that these compounds are much less stimulating when compared with cocaine at comparable doses. In drug-discrimination studies these selected compounds incompletely generalized from the cocaine stimulus in mice trained to discriminate 10 mg/kg cocaine from vehicle.

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

“…132 Preliminary behavioral evaluation of additional GBR 12909 analogs have demonstrated that some of these compounds are not cocaine-like or GBR 12909-like in locomotor activity or drug discrimination studies. 122 These studies more closely resemble those behavioral studies that we have conducted on both the benztropines and rimcazoles wherein most of these ligands do not appear to behave like cocaine, despite binding with high affinity to the DAT. [58][59][60][61]108 …”

“…30,36,39 Modifications of the propyl linker between the piperazine ring and the diphenyl ether have also been made with success. 117,121,122 These modifications have suggested that the role of the oxygen in the diphenyl ether is simply as a spacer atom and can be replaced with nitrogen or a methylene group. 121,122 In summary, the GBR 12909 molecule has provided fertile ground for chemical modification resulting in many high affinity and selective DAT ligands.…”

“…117,121,122 These modifications have suggested that the role of the oxygen in the diphenyl ether is simply as a spacer atom and can be replaced with nitrogen or a methylene group. 121,122 In summary, the GBR 12909 molecule has provided fertile ground for chemical modification resulting in many high affinity and selective DAT ligands. In general, structure-activity relationships at the DAT for the rimcazole analogues appear to follow that of the GBR 12909 analogues.…”

Dual Probes for the Dopamine Transporter and σ1 Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

“…3,[12][13][14][15][16] In our initial series of rimcazole analogues, the most potent DAT inhibitor, 1 (K i ) 61 nM), showed moderately potent σ 1 binding affinity (K i ) 97 nM) and was ∼3-fold less potent at SERT (K i ) 219 nM) and 60-fold selective over NET. 11 Several rimcazole analogues (1-4) were evaluated in animal models of cocaine abuse and toxicity.…”

Synthesis of Tricyclic Condensed Rings Incorporating the Pyrazole or Isoxazole Moieties Bonded to a 4-Piperidinyl Substituent

“…The chloroketone 1a was a commercial compound. 6-Chloro-3,4-dihydronaphthalen-1-one (1b) [6], 7-chloro-2,3,4,5-tetrahydrobenzocyclo-heptan-1-one (1c) [7], N-Boc-nipecotic acid [8] and the piperidines 18 [10] and 19 [11] were obtained following the corresponding literature procedures.…”