A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.

A series of 26 derivatives of the novel muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for muscarinic and antimuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic-potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure-activity relationship models were developed for this series of substituted benzofuranyl derivatives.

Donor Substituted 2,4‐Diazacyclopentadienones and Indigoid 1,3,5,7‐Tetraazafulvalenes Hydrolysis of tris(diethylamino)imidazolylium chloride gives rise to 2,5‐bis‐diethyl‐amino‐4H‐imidazolin‐4‐one; thiolysis leads, depending on conditions, to 2,5‐bis‐diethylamino‐4H‐imidazolin‐4‐thione or potassium 2,6‐bis‐diethylamino‐1,3,5,7‐tetraazafulvalene‐4,8‐dithiolate. The latter can be protonated to form green 2,6‐bis(dimethylamino)‐3,4,7,8‐tetrahydro‐1,3,5,7‐tetraaza‐fulvalen‐4,8‐dithione, a new indigoid compound, and alkylated to give blue 2,6‐bis‐diethylamino‐4,8‐bis‐alkylthio‐1,3,5,7‐tetraazafulvalenes. Treatment of 2,5‐bis‐diethylamino‐4H‐imidazolin‐4‐thione with copper furnishes 2,6,4,8‐tetrakis‐diethylamino‐1,3,5,7‐tetraazafulvalene. – Oxidation of 2,6‐bis‐dimethylamino‐3,4,7,8‐tetrahydro‐1,3,5,7‐tetraazafulvalen‐4,8‐dithione gives rise to (2,2′‐bis‐diethylamino‐4,4′‐bi(4H‐imidazol)‐5,5′‐dithione, corresponding to dehydroindigo, and reduction leads to a colorless compound, corresponding to leucoindigo.

A number of tetrahydrofuran analogues of 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane] (1) have been prepared with the aim to obtain information about the relative importance of each of the oxygens in 1 for efficacy and for selectivity. In addition, the dimethyl and desmethyl analogues of 1 were prepared. The new compounds were compared to cis- and trans-1 with regard to their ability to displace (-)-[3H]-3-quinuclidinyl benzilate ((-)-[3H]QNB) from muscarinic receptors in cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs. Functional studies were made on isolated guinea pig bladder and ileum. The new compounds exhibited both lower affinity and efficacy than cis-1. A conformational study was performed, and the effects of steric and electronic factors on the biological activity of the compounds are discussed.

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