ABSTRACT
A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-piperidines and 4-[2-[(bisphenyl)methoxy]ethyl]-piperidines with different types of substituents in the phenylpropyl side-chain were synthesized and examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). All of the compounds showed high binding affinities for the DAT in the low to subnanomolar range. Their ability to bind to the SERT and the NET, while maintaining their high affinity for the DAT, could be altered by substitution in positions C2 and C3 of the phenylpropyl side-chain. This approach gave rise to a new set of compounds with selectivity for the DAT, the DAT and the SERT, or the DAT and the NET. Six compounds (7, 9, 11, 12, 14, and 20) with relatively low SERT/DAT ratios were selected for additional study in biogenic amine uptake inhibition assays based on the biogenic amine transporter binding results. Some of the new ligands can serve as pharmacological tools to block DAT or DAT and another transporter simultaneously.
Subject(s)
Dopamine Plasma Membrane Transport Proteins/metabolism , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Piperidines/chemical synthesis , Serotonin Plasma Membrane Transport Proteins/metabolism , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Ligands , Piperidines/chemistry , Piperidines/pharmacology , Radioligand Assay , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl-1-benzylpiperidines were examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Binding results indicated that the presence of an electron-withdrawing group in the C(4)-position of the N-benzyl group is beneficial for binding to the DAT. Several analogues have been identified with high affinity for the DAT, up to 500-fold selectivity over the SERT and about 170-fold selectivity over the NET in binding and uptake inhibition assays.
Subject(s)
Dopamine Uptake Inhibitors/chemical synthesis , Dopamine/metabolism , Membrane Transport Modulators , Membrane Transport Proteins/metabolism , Nerve Tissue Proteins , Piperazines/chemistry , Piperidines/chemical synthesis , Carrier Proteins/metabolism , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Membrane Glycoproteins/metabolism , Norepinephrine/metabolism , Norepinephrine Plasma Membrane Transport Proteins , Piperidines/chemistry , Piperidines/pharmacology , Protein Binding , Radioligand Assay , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins , Structure-Activity Relationship , Symporters/antagonists & inhibitors , Symporters/metabolismABSTRACT
A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethylpiperidines were examined for their ability to bind to the dopamine transporter (DAT), the norepinephrine transporter, and the serotonin transporter (SERT). In particular, the role of the N-substituent on affinity and selectivity for the DAT was probed. 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl-1-(2-naphthylmethyl)piperidine was found to possess subnanomolar affinity (K(i) = 0.7 nM) and good selectivity for the DAT (SERT/DAT = 323).
Subject(s)
Dopamine/metabolism , Membrane Transport Proteins/metabolism , Nerve Tissue Proteins , Piperazines/chemical synthesis , Carrier Proteins/metabolism , Dopamine Plasma Membrane Transport Proteins , Membrane Glycoproteins/metabolism , Norepinephrine/metabolism , Norepinephrine Plasma Membrane Transport Proteins , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins , Structure-Activity Relationship , Symporters/metabolismABSTRACT
The 8beta-unsubstituted and substituted analogues of hydrocodone indole and hydromorphone indole were synthesized and their binding affinities to opioid receptors were determined. Introduction of an 8beta-methyl group into the indolomorphinan nucleus increased affinity at all opioid receptors. 6,7-Dehydro-4,5alpha-epoxy-8beta-methyl-6,7,2',3'-indolomorphinan (9) was found to be a delta antagonist with subnanomolar affinity (0.7 nM) for the delta-opioid receptor, and to have good delta-selectivity (mu/delta=322).
