Design, synthesis, and biological evaluation of novel non-piperazine analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines as dopamine transporter inhibitors.
A series of novel diamine, amine-amide, and piperazinone analogues of N-[2-(bisarylmethoxy)ethyl]-N'-(phenylpropyl)piperazines, GBR 12909 and 12935, were synthesized and evaluated as inhibitors of presynaptic monoamine neurotransmitter transporters. The primary objective of the study was to determine the structural requirements for selectivity of ligand binding and potency for neurotransmitter reuptake inhibition. In general, the target compounds retained transporter affinity; however, structural variations produced significant effects on reuptake inhibition and transporter selectivity. For example, analogues prepared by replacing the piperazine ring in the GBR structure with an N, N'-dimethylpropyldiamine moiety displayed enhanced selectivity for binding and reuptake inhibition at the norepinephrine (NE) transporter site (e.g. 4 and 5). Congeners in which the amide nitrogen atom was attached to the aralkyl moiety of the GBR molecule showed moderate affinity (K(i) = 51-61 nM) and selectivity for the dopamine transporter (DAT) site. In contrast, introduction of a carbonyl group adjacent to either nitrogen atom of the piperazine ring (e.g. 25 and 27) was not well tolerated. From the compounds prepared, analogue 16 was selected for further evaluation. With this congener, locomotor activity induced by cocaine at a dose of 20 mg/kg was attenuated with an AD(50) (dose attenuating cocaine-induced stimulation by 50%) of 60.0 +/- 3.6 mg/kg.
Choi
S W
SW
Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Elmaleh
D R
DR
Hanson
R N
RN
Fischman
A J
AJ
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000494:pharmacology
D000577:Amides; D000588:Amines; D015306:Biogenic Monoamines; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493214:SLC6A3 protein, human; C493215:Slc6a3 protein, mouse; C043425:vanoxerine; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; D004298:Dopamine