title: Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
abstract: Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D018491:Dopamine Agonists / Q000138:chemical synthesis*; D015195:Drug Design; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D012680:Sensitivity and Specificity; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; C493593:DRD3 protein, human; D018491:Dopamine Agonists; C475720:FAUC 725; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3