Structurally diverse molecules, such as alcuronium, gallamine, and tubocurarine as well as W84 and WDUO, are known to interact allosterically with ligand binding to muscarinic M2 acetylcholine receptors. Preliminary molecular modeling studies revealed two positive charges in the middle and two lateral aromatic areas to be essential elements of a high allosteric potency. To find out the optimum distances between these pharmacophoric elements, a systematic variation of the spacer in the series of W84, WDUO, and IWDUO compounds was performed. The allosteric reduction of the rate of dissociation of the antagonist [3H]-N-methylscopolamine from porcine heart M2 receptors served as a test system. The minimal essential distance between the positive charges was found to be 10 A. The length of the peripheral spacers connecting the positive charge and the lateral aromatic moiety appears to depend on the chemical functionality; the peripheral spacers have to be long and flexible enough to position the aromatic skeletons in the spatial neighborhood of the alkane middle chain: in the case of an oxime ether containing peripheral spacer, six atoms are required, and in the case of an alkane chain, four carbon atoms are necessary to adopt the pharmacophoric S-shape conformation.

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3,7-Diazabicyclo[3.3.1]nonan-9-ones having aryl rings in positions 2 and 4 with systematically varied substituents were synthesized using a double Mannich procedure. Radioligand binding assays were performed to measure the affinity of the compounds to the mu-, delta-, and kappa-opioid receptors. The affinity of all 2, 4-diphenyl-substituted 3,7-diazabicyclo[3.3.1]nonan-9-ones to the mu- and delta-receptors was found to be low. In contrast, with exception of the nitro- and cyanophenyl-substituted compounds, most of the diazabicycles showed considerable affinity for the kappa-receptor. In particular, the m-fluoro-, p-methoxy-, and m-hydroxy-substituted compounds have an affinity in the submicromolar range. Due to solubility problems in aqueous media, salts of HZ2 were synthesized. The methiodide shows high kappa-affinity and may, thus, be a promising candidate for development of a peripheral kappa-agonist, e.g. for use in the case of rheumatoid arthritis.

The stereochemistry the 2,4-di-arene substituted 3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-dicarboxylate skeleton was found to be regulated by the kind of substituents attached to the arene rings as well as to the nitrogens N3 and N7. Conformational isomers, i.e., chair/chair, boat/chair and chair/boat, in addition to cis/trans configurational isomerism with respect to the arene rings were reported. Since the analgesic potency of the diazabicyclononanones, which is related to their affinity toward the κ-opioid receptor, is governed by the stereochemistry of the molecules, the influence of the substituents at nitrogen N7 was studied herein. The various differently N7 substituted diazabicyclononanones were found to crystallise in a highly symmetrical chair/chair conformation. However, beside HZ2 none of the compounds exhibits high affinity to the κ receptor. In contrast, some compounds with affinity to the µ receptor could be identified. In addition, the N7-(4-carboxybenzyl) substituted compound was found to have affinity to the δ receptor in the submicromolar range of concentration.

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