Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
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.
Löber
Stefan
S
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Hübner
Harald
H
Gmeiner
Peter
P
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
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