The Power of Visual Imagery in Drug Design. Isopavines as a New Class of Morphinomimetics and Their Human Opioid Receptor Binding Activity

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.

Structure‐Based Organic Synthesis of Drug Prototypes: A Personal Odyssey

“…Subsequent introduction of aromatic substituents on ent-97 led to analogues exhibiting activity toward the m-receptor in the low nanomolar range. [181] Since the discovery of stereochemistry and its relevance to organic synthesis, it has been customary for synthetic chemists to build molecular models and to study their three-dimension- ality in space. Although nowadays the same can be accomplished on the computer screen with the added numerical bonus of energy data, there is still a nostalgic if not pedagogically pleasing merit of actually touching and "playing" with ball-and-stick-type molecular models.…”

Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings

“…To meet this urgent need, the development of diversity-oriented synthesis approach for the rapid creation of complex molecules in the library has received increasing attention in both medicinal chemistry and chemical synthesis123. Although benzannulated medium- or medium-bridged rings constitute the basic skeletons of many important naturally occurring and biologically active molecules456789, they are really rare among the top 200 drugs10. The main reason is probably the difficulty in developing general strategies for the diversity-oriented synthesis of such library of structures111213.…”

“…Therefore, this discovery will be a highly flexible tool for diverse collection of a variety of medium-sized rings and related bridged ring libraries with over 37 distinct scaffolds as well as the identification of some compounds with potent inhibitory activity against the cancer cell or derivative of human embryonic kidney lines. Noteworthy is that many formed benzannulated medium-sized or medium-bridged rings constitute the key synthetic intermediates and unnatural analogues of many important naturally occurring and biologically active molecules such as benzannulated cyclooctanes (antiarrhythmic, antidiarrheal, antiallergic and anti-inflammatory)4, nonadride family (byssochlamic acid, heveadride, rubratoxin B, glaucanic and glauconic acid with antifungal, antimicrobial and antitumor activities)56, isopavine family (neurological disorders inhibition)78 and colchicine derivatives (anticancer activity)9 (Fig. 2).…”

Probing the “additive effect” in the proline and proline hydroxamic acid catalyzed asymmetric addition of nitroalkanes to cyclic enones

“…Traditionally, the design concept for a ligand molecule relies heavily on the manual manipulation of molecular models, or computer-aided 3D visualization of desired proximity and stereodifferentiating effects. 2 Once a plausible mechanistic scenario is conceived on paper, on the computer screen, or in the mind's eye, 3 it is only through experimentation that the validity of the design concept can be verified. It is at this point that weeks or months of heightened anticipation for a favorable enantio-or diastereoselectivity can be most rewarding, or bitterly disappointing.…”