Structural studies on hydrogen-bonding receptors for barbiturate guests that use metal ions as allosteric inhibitors

Receptor 1 was designed to bind barbiturate substrates through a six-point hydrogen-bonding motif only in the absence of metal allosteric cofactors. It was predicted that the binding of metal ions by bipyridine ligands in 1 would result in a geometric change in the receptor to inhibit substrate recognition. However, receptor 1 showed minimal affinity for the barbiturate guests even in the absence of the metal. Binding studies on model compounds 2, 3, 5, and 6 revealed that the inactivity of 1 is due to an intramolecular hydrogen bond between the N-H donor groups and the nitrogen atoms on the first heterocycle of the bipyridine ligands. This intramolecular hydrogen-bonding was eliminated by altering the position of the tether between the bipyridine ligands and the active site to produce receptor 7. Consequently, the high affinity exhibited by 7 for the barbiturate substrate (K-a = 2.8 +/- 0.7 x 10(3) M-1 in 9:1 CD2Cl2/CD3CN) was significantly reduced by the addition of Zn-II ions as a negative allosteric co-factor. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004).