The power of visual imagery in drug design. Isopavines as a new class of morphinomimetics and their human opioid receptor binding activity.
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.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, Succersale Centre-Ville, Montréal, Québec, Canada. stephen.hanessian@umontreal.ca
Parthasarathy
Saravanan
S
Mauduit
Marc
M
Payza
Kemal
K
D001392:Azocines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009022:Morphine Derivatives / Q000737:chemistry*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D013237:Stereoisomerism
D001392:Azocines; D009022:Morphine Derivatives; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu