A 1H nmr study of the amide-bond conformational equilibrium in pirenzepine

The hindered rotation about the exocyclic amide bond of pirenzepine has been studied using 1H nuclear magnetic resonance spectroscopy. The ratios of the two slowly interconverting conformations (1:1.76 at 2 degrees C and 1:2.37 at 30 degrees C) and the rate of interconversion (1 +/- 0.5 s-1 at 20 degrees C and 247 +/- 20 s-1 at 80 degrees C with delta g ++80 = 71 KJ mol-1) have been measured at various temperatures. The observed rapid rates of interconversion allow us to eliminate the rate of conformational selection of forms II and III as a major contributor to the slow phase of the binding kinetics observed when pirenzepine binds to muscarinic receptors from rat brain (Stockton, Birdsall, Hulme and Burgen, unpublished results).