Further exploration of 1-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]piperazine (GBR 12909): role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter.
A series of N-aromatic, N-heteroaromatic, and oxygenated N-phenylpropyl derivatives of 1-(2-benzhydryloxyethyl)-piperazine and 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]piperazine, analogues of GBR 12909 (1a) and 12935 (1b), was synthesized and examined for their dopamine (DAT) and serotonin (SERT) transporter binding properties. One of these compounds, racemic 3-[4-(2-benzhydryloxyethyl)piperazin-1-yl]-1-(3-fluorophenyl)-propan-1-ol (33), had DAT affinity as good as, or better than, GBR 12909 and 12935, and was more selective for DAT over SERT than the GBR compounds. Both trans- (43) and cis- (47) (+/-)-2-(4-[2-[bis-(4-fluorophenyl)-methoxy]ethyl]piperazin-1-ylmethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol had relatively good SERT selectivity and, as well, showed high affinity for SERT.
Lewis
David
D
Laboratory of Medicinal Chemistry, NIDDK, NIH, Bethesda, MD 20892, USA.
Zhang
Ying
Y
Prisinzano
Thomas
T
Dersch
Christina M
CM
Rothman
Richard B
RB
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D000438:Alcohols; D002352:Carrier Proteins / Q000737:chemistry* / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008352:Mannich Bases; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000187:drug effects; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship
D000438:Alcohols; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D006571:Heterocyclic Compounds; D008352:Mannich Bases; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; C043425:vanoxerine; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine