From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.
Article Details
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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
Drug Target Kind Organism Pharmacological Action Actions Meperidine Mu-type opioid receptor Protein Humans UnknownAgonistDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Fentanyl Kappa-type opioid receptor IC 50 (nM) 1580 N/A N/A Details Fentanyl Mu-type opioid receptor IC 50 (nM) 1.3 N/A N/A Details Meperidine Kappa-type opioid receptor IC 50 (nM) 2370 N/A N/A Details Meperidine Mu-type opioid receptor IC 50 (nM) 315 N/A N/A Details Methadone Mu-type opioid receptor IC 50 (nM) 4.1 N/A N/A Details Nalbuphine Kappa-type opioid receptor IC 50 (nM) 83 N/A N/A Details Nalbuphine Mu-type opioid receptor IC 50 (nM) 1 N/A N/A Details Naloxone Kappa-type opioid receptor IC 50 (nM) 1.5 N/A N/A Details Naloxone Mu-type opioid receptor IC 50 (nM) 2 N/A N/A Details