Relative binding orientations of adenosine A1 receptor ligands — A test case for Distributed Multipole Analysis in medicinal chemistry

Summary The electrostatic properties of adenosine-based agonists and xanthine-based antagonists for the adenosine A₁ receptor were used to assess various proposals for their relative orientation in the unknown binding site. The electrostatic properties were calculated from distributed multipole representations of SCF wavefunctions. A range of methods of assessing the electrostatic similarity of the ligands were used in the comparison. One of the methods, comparing the sign of the potential around the two molecules, gave inconclusive results. The other approaches, however, provided a mutually complementary and consistent picture of the electrostatic similarity and dissimilarity of the molecules in the three proposed relative orientations. This was significantly different from the results obtained previously with MOPAC AM1 point charges. In the standard model overlay, where the aromatic nitrogen atoms of both agonists and antagonists are in the same position relative to the binding site, the electrostatic potentials are so dissimilar that binding to the same receptor site is highly unlikely. Overlaying the N⁶-region of adenosine with that near C8 of theophylline (the N⁶-C8 model) produces the greatest similarity in electrostatic properties for these ligands. However, N⁶-cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) show greater electrostatic similarity when the aromatic rings are superimposed according to the flipped model, in which the xanthine ring is rotated around its horizontal axis. This difference is mainly attributed to the change in conformation of N⁶-substituted adenosines and could result in a different orientation for theophylline and DPCPX within the receptor binding site. However, it is more likely that DPCPX also binds according to the N⁶-C8 model, as this model gives the best steric overlay and would be favoured by the lipophilic forces, provided that the binding site residues could accommodate the different electrostatic properties in the N⁶/N7-region. Finally, we have shown that Distributed Multipole Analysis (DMA) offers a new, feasible tool for the medicinal chemist, because it provides the use of reliable electrostatic models to determine plausible relative binding orientations.Abbreviations DMA distributed multipole analysis - SCF self-consistent field - CPA N⁶-cyclopentyladenosine - DPCPX 1,3-dipropyl-8-cyclopentylxanthine - R-PIA R-1-phenyl-2-propyladenosine - S-PIA S-1-phenyl-2-propyladenosine     

Michael addition reactions with eta2-coordinated anisoles: controlling the stereochemistry of the para and benzylic carbons

Several eta(2)-coordinated anisole complexes were treated with various Michael acceptors in the presence of a Lewis or Bronsted acid to generate stable 4H-anisolium complexes. These reactions were found to proceed with high stereochemical control with predictable outcomes, provided that the moderate acid (NH(2)Ph(2))OTf was used and the complex was dissolved in an acidic solution. The stereochemistry is shown to originate from an unexpectedly high preference for one coordination diastereomer of the anisole complex in the solid state and a Diels-Alder like transition state for the Michael reaction.     

Selective electroless metal deposition using microcontact printing of phosphine-phosphonic acid inks

We report a low-cost approach to selectively deposit films of nickel and copper on glass substrates. Our approach uses microcontact printing of organic inks containing phosphonic acid groups to bind the ink to a glass substrate and phosphine groups to bind a colloidal catalyst that initiates electroless metallization. We demonstrate this procedure by fabricating patterned nickel and copper films with areas as large as 15 cm2 and minimum feature sizes of approximately 2 microm. We present studies on the use of two ink types, an oligomer and a bifunctional molecule, and demonstrate that pattern quality and adhesion of the metallized films depends on the molecular weight of the ink and the ratio of phosphine and phosphonic acid groups.     

Novel podands and macrocycles with diacetal (tetraoxadecalin) cores: synthesis, structure, stereochemistry and cation inclusion

A series of functionalized 2,6-dialkyl-cis-1,3,5,7-tetraoxadecalin podands (3-10, alkyl = hydroxy-, mesyloxy-, halo-, azido- and aminomethyl and -ethyl) were prepared, characterized, and used as precursors for a new and interesting class of macrocycles and cryptands (12-21), with the aim to use these as host-guest inclusion systems. Extensive spectroscopic work was performed, structural endorsement was obtained from X-ray diffraction analyses and further insight into the structures was obtained from theoretical/computational studies. A number of macrocycles in the series exhibited good complexation with alkaline-earth metal ions.     

Modification of 1-substituents in the 2-azabicyclo[2.1.1]hexane ring system; approaches to potential nicotinic acetylcholine receptor ligands from 2,4-methanoproline derivatives

Successful nucleophilic substitution at a methylene attached to the bridgehead (1-) position of the 2-azabicyclo[2.1.1]hexane ring system opens the way to construction of novel derivatives having a wider range of functional groups attached to the 1-position via a methylene "spacer" (including the beta-amino acid homologue of 2,4-methanoproline) and provides access to epibatidine analogues containing heterocyclic substituents and also to further homologation at the 1-position. Displacements with loss of a nucleofuge (e.g., loss of mesylate anion from the 1-mesyloxymethyl derivative) require thermal activation but proceed without the rearrangement initially anticipated in such a strained bicyclic ring system. A novel tricyclic carbamate intermediate 17 has been isolated; nucleophilic attack on 17 leads directly to the isolation of N-deprotected substitution products (with concomitant decarboxylation).