From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.

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Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Deprez B

From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.

J Med Chem. 2001 Oct 11;44(21):3378-90.

PubMed ID
11585443 [ View in PubMed
]
Abstract

Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
MeperidineMu-type opioid receptorProteinHumans
Unknown
Agonist
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
FentanylKappa-type opioid receptorIC 50 (nM)1580N/AN/ADetails
FentanylMu-type opioid receptorIC 50 (nM)1.3N/AN/ADetails
MeperidineKappa-type opioid receptorIC 50 (nM)2370N/AN/ADetails
MeperidineMu-type opioid receptorIC 50 (nM)315N/AN/ADetails
MethadoneMu-type opioid receptorIC 50 (nM)4.1N/AN/ADetails
NalbuphineKappa-type opioid receptorIC 50 (nM)83N/AN/ADetails
NalbuphineMu-type opioid receptorIC 50 (nM)1N/AN/ADetails
NaloxoneKappa-type opioid receptorIC 50 (nM)1.5N/AN/ADetails
NaloxoneMu-type opioid receptorIC 50 (nM)2N/AN/ADetails