Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.

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Elsner J, Boeckler F, Heinemann FW, Hubner H, Gmeiner P

Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.

J Med Chem. 2005 Sep 8;48(18):5771-9.

PubMed ID
16134944 [ View in PubMed
]
Abstract

Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PramipexoleDopamine D2 receptorKi (nM)6300N/AN/ADetails
PramipexoleDopamine D2 receptorKi (nM)21N/AN/ADetails
PramipexoleDopamine D2 receptorKi (nM)1900N/AN/ADetails
PramipexoleDopamine D3 receptorEC 50 (nM)1.5N/AN/ADetails
PramipexoleDopamine D3 receptorKi (nM)38N/AN/ADetails
PramipexoleDopamine D3 receptorKi (nM)0.88N/AN/ADetails
PramipexoleDopamine D4 receptorKi (nM)8.1N/AN/ADetails
PramipexoleDopamine D4 receptorKi (nM)130N/AN/ADetails