Structurally constrained hybrid derivatives containing octahydrobenzo[g or f]quinoline moieties for dopamine D2 and D3 receptors: binding characterization at D2/D3 receptors and elucidation of a pharmacophore model.
A series of structurally constrained analogues based on hybrid compounds containing octahydrobenzo[g or f]quinoline moieties were designed, synthesized, and characterized for their binding to dopamine D2 and D3 receptors expressed in HEK-293 cells. Among the newly developed constrained molecules, trans-octahydrobenzo[f]quinolin-7-ol (8) exhibited the highest affinity for D2 and D3 receptors, the (-)-isomer being the eutomer. Interestingly, this hybrid constrained version 8 showed significant affinity over the corresponding nonhybrid version 1 (representing a constrained version of the aminotetralin structure only) when assayed under same conditions (K(i) of 49.1 and 14.9 nM for 8 vs 380 and 96.0 nM for 1 at D2 and D3, respectively). Similar results were found with other lead hybrid compounds, indicating a contribution of the piperazine moiety in the observed enhanced affinity. On the basis of the data of new lead constrained derivatives and other lead hybrid derivatives developed by us, a unique pharmacophore model was proposed consisting of three pharmacophoric centers, two with aromatic/hydrophobic and one with cationic features.
Brown
Dennis A
DA
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48202, USA.
Kharkar
Prashant S
PS
Parrington
Ingrid
I
Reith
Maarten E A
ME
Dutta
Aloke K
AK
D055592:Biophysical Phenomena; D002412:Cations; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004298:Dopamine / Q000737:chemistry; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D011485:Protein Binding; D011804:Quinolines / Q000737:chemistry*; D011807:Quinolizines / Q000737:chemistry*; D017448:Receptors, Dopamine D2 / Q000737:chemistry*; D050637:Receptors, Dopamine D3 / Q000737:chemistry*
D002412:Cations; D018492:Dopamine Antagonists; D011804:Quinolines; D011807:Quinolizines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C435784:octahydrobenzo(c)quinolizin-3-one; C037219:quinoline; D004298:Dopamine