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The highly complex practice of building successful community coalitions is explored. Key dimensions related to coalition success are identified and best practices are delineated. Nine dimensions are explored that are critical to coalition success: coalition readiness, intentionality, structure and organizational capacity, taking action, membership, leadership, dollars and resources, relationships, and technical assistance. Two coalition case studies follow the discussion of dimensions and illustrate the journey traveled to create successful community coalitions.

To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.