Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: role of amino, fluoro, hydroxyl, methoxyl, methyl, methylene, and oxo substituents on affinity for the dopamine and serotonin transporters.
Novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp (2) hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT.
Hsin
Ling-Wei
LW
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Number 1, Section 1, Jen-Ai Road, Room 1336, Taipei, Taiwan 10018. lwhsin@ntu.edu.tw
Chang
Li-Te
LT
Rothman
Richard B
RB
Dersch
Christina M
CM
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; C043425:vanoxerine; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine