GBR compounds and mepyramines as cocaine abuse therapeutics: chemometric studies on selectivity using grid independent descriptors (GRIND).
Cocaine is one of the most widely abused drugs in the industrial world. Substantial evidence has accumulated that the dopamine transporter (DAT) is a key target for cocaine regarding its reinforcing effects. This work describes the application of chemometric methods to a data set of 54 N(1)-benzhydryl-oxy-alkyl-N(4)-phenyl-alk(en)yl-piperazines (GBR compounds) and chemically related mepyramines as putative candidates in cocaine abuse therapy. The aim of the study is to gain insight into the structural requirements that determine the affinity of the data set molecules to the DAT and the serotonin transporter (SERT) as well as their inhibitory potency on dopamine uptake. The compounds in the dataset are described using the recently developed GRID independent descriptors (GRIND), which allow one to obtain fast three-dimensional quantitative structure-activity relationship models without the need of aligning and superimposing the structures; the results are interpreted in a convenient pharmacophoric-like fashion. In the first part of the work, the selectivity of the database molecules for DAT binding vs dopamine reuptake inhibition is investigated. In the second part, the selectivity of the compounds for DAT binding vs SERT binding is studied. In both cases, significant models are obtained, which define the structural features responsible for the respective selectivity profiles. Moreover, the information has potential interest for the design of new derivatives with improved selectivity.
Benedetti
Paolo
P
Dipartimento di Chimica, Laboratorio di Chemiometria, Università di Perugia, Via Elce di Sotto, 10, I-06123 Perugia, Italy.
Mannhold
Raimund
R
Cruciani
Gabriele
G
Pastor
Manuel
M
D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011738:Pyrilamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D011738:Pyrilamine; D004298:Dopamine