Dopamine autoreceptor agonists: computational studies, synthesis and biological investigations

Functionally Selective Dopamine D2, D3Receptor Partial Agonists

“…On the basis of recent findings indicating that the nature of the heterocyclic appendage of 2a derivatives is associated with the ratio of G-protein activation and β-arrestin-promoted signaling, , the quinolinone scaffold was bioisosterically replaced. Since an incorporation of the pyrazolo[1,5- a ]pyridine unit using different attachment points proved to be beneficial for fine-tuning the dopaminergic properties of 1,4-DAPs, − we prepared and studied a collection of regioisomeric target compounds of type 1 , formally hybridizing the antipsychotic 2a , the drug candidate 2b , and our previously described dopaminergics of type 3 (Figure )…”

Conjugated Enynes as Nonaromatic Catechol Bioisosteres: Synthesis, Binding Experiments, and Computational Studies of Novel Dopamine Receptor Agonists Recognizing Preferentially the D3Subtype

“…The dopaminergic effects of ergoline derivatives including SAR studies with ergoline partial structures show that indole or pyrrole rings as well as aza analogues thereof can also mimic the catechol moiety of DA. [6][7][8][9] Heterocyclic bioisosteres play also an important role in the field of 5-HT receptor and adrenoreceptor agonists. 10,11 However, in all cases aromatic substructures are involved.…”

“…In this case, an aromatic heterocyclic system has been used as a bioisosteric surrogate for the catechol nucleus. The dopaminergic effects of ergoline derivatives including SAR studies with ergoline partial structures show that indole or pyrrole rings as well as aza analogues thereof can also mimic the catechol moiety of DA. − Heterocyclic bioisosteres play also an important role in the field of 5-HT receptor and adrenoreceptor agonists. , However, in all cases aromatic substructures are involved. As far as we know, nonaromatic agonists of DA receptors, 5-HT receptors, or adrenoreceptors have not been described, yet.…”

Highly Potent 5-Aminotetrahydropyrazolopyridines: Enantioselective Dopamine D3 Receptor Binding, Functional Selectivity, and Analysis of Receptor−Ligand Interactions

“…Fused pyrazole derivatives have been described as excellent molecular scaffolds in dopaminergic bi- and tricyclic ergoline analogues. ,,, Efficient synthetic pathways to the fused pyrazole derivatives of types 5 and 7 were elaborated. Starting from N -amino-4-benzyloxypyridinium mesitylene sulfonate 8 , we followed our previously described protocol involving 1,3-dipolar cycloaddition with methyl propiolate under oxidative conditions, simultaneous cleavage of the benzyl ether function, removal of the carboxylic ester group, catalytic hydrogenation, activation of the secondary alcohol, nucleophilic displacement with sodium azide, and subsequent reduction to afford the primary amine 9 in racemic form (Scheme ).…”

“…After the mixture was stirred for 45 min at 0 °C, aqueous HCl (1 N, 2 mL) and saturated NaHCO 3 (6 mL) were added. After addition of diethyl ether, the organic layer was dried (MgSO 4 ) and evaporated and the residue was purified by flash chromatography (CH 2 Cl 2 /MeOH 97/3) to give pure 4-propylamino-4,5-dihydro-3 H -pyrazolo[4,5,1- i , j ]quinoline (26 mg, 53%) as a colorless oil …”