The power of visual imagery in drug design. Isopavines as a new class of morphinomimetics and their human opioid receptor binding activity.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
CodeineKappa-type opioid receptorIC 50 (nM)15000N/AN/ADetails
CodeineMu-type opioid receptorIC 50 (nM)105N/AN/ADetails
LevorphanolKappa-type opioid receptorIC 50 (nM)4N/AN/ADetails
LevorphanolMu-type opioid receptorIC 50 (nM)0.13N/AN/ADetails
MorphineKappa-type opioid receptorIC 50 (nM)1705.1N/AN/ADetails
MorphineMu-type opioid receptorIC 50 (nM)0.57N/AN/ADetails