TY - JOUR ID - 2160 TI - Diazabicyclononanones, a potent class of kappa opioid analgesics JO - Farmaco PY - 2002 SP - 531-534 AU - Holzgrabe, U. AU - Cambareri, A. AU - Kuhl, U. AU - Siener, T. AU - Brandt, W. AU - Straßburger, W. AU - Friderichs, E. AU - Englberger, W. AU - Kögel, B. AU - Haurand, M. AU - VL - 57 UR - DO - 10.1016/S0014-827X(02)01243-0 AB - The 1,5-dimethyl 3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo[3.3.1]nonane-1,5-dicarboxylate, HZ2, has a high and selective affinity for the kappa opioid receptor and an antinociceptive activity comparable to morphine. In addition, it is characterized by a long duration of action and a high oral bioavailability. QSAR studies within series of kappa agonists revealed a chair-boat conformation of a double protonated HZ2 characterized by an almost parallel orientation of the C9 carbonyl group and the N7-H group and at least one aromatic ring to be the pharmacophoric arrangement. Structural variations showed that the pyridine rings in 2 and 4 position can be replaced with p-methoxy-, m-hydroxy- and m-fluoro-substituted phenyl rings. However, all other substituents have to be kept the same for a high affinity to the kappa receptor. A2 - C1 - Bioorganic Chemistry ER -