The power of visual imagery in drug design. Isopavines as a new class of morphinomimetics and their human opioid receptor binding activity.
Article Details
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Hanessian S, Parthasarathy S, Mauduit M, Payza K
The power of visual imagery in drug design. Isopavines as a new class of morphinomimetics and their human opioid receptor binding activity.
J Med Chem. 2003 Jan 2;46(1):34-48.
- PubMed ID
- 12502358 [ View in PubMed]
- Abstract
The importance of visual imagery and relational thinking manifests itself in a heuristic approach to the design and synthesis of potential morphinomimetics as agonists of the human mu receptor. The well-known class of alkaloids represented by the isopavine nucleus has a topological resemblance to the morphine skeleton, especially when viewed in a particular way. Enantiopure isopavines can be readily obtained from a 1,2 Stevens rearrangement of 13-substituted dihydromethanodibenzoazocines, prepared in four steps from d- and l-amino acids. Consideration of the topology and the expected orientation of the nitrogen lone pair for a better overlap with morphine necessitates the utilization of d-amino acids. By variation of the substituents on the aromatic rings and a judicious choice of ring substituents, it is possible to obtain low nanomolar binding to the human mu receptor while maintaining good to excellent mu/delta selectivity. Agonist-like activity is indicated in a functional assay for one of the analogues originally derived from d-alanine as a precursor. X-ray crystal structures of several compounds corroborate stereochemistries and overall topologies.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Codeine Kappa-type opioid receptor IC 50 (nM) 15000 N/A N/A Details Codeine Mu-type opioid receptor IC 50 (nM) 105 N/A N/A Details Levorphanol Kappa-type opioid receptor IC 50 (nM) 4 N/A N/A Details Levorphanol Mu-type opioid receptor IC 50 (nM) 0.13 N/A N/A Details Morphine Kappa-type opioid receptor IC 50 (nM) 1705.1 N/A N/A Details Morphine Mu-type opioid receptor IC 50 (nM) 0.57 N/A N/A Details