These findings confirm that only selective 5-HT1A receptor antagonists have favourable effects on the bladder, inducing an increase in bladder capacity with no derangement of bladder contractility.
Novel 1,4-dioxane compounds structurally related to WB 4101 (1) were prepared in order to investigate the possibility that the quite planar 1,4-benzodioxane template of 1 might be replaced by the less conformationally constrained 1,4-dioxane ring. The biological profiles of the new compounds were assessed using binding assays at human cloned alpha 1-adrenoreceptor (alpha 1-AR) subtypes and 5-HT 1A receptors, expressed in Chinese hamster ovary and HeLa cell membranes, respectively, and by functional experiments in isolated rat vas deferens (alpha 1A), spleen (alpha 1B), and aorta (alpha 1D). Moreover, the cytotoxic effects of the novel compounds were determined in PC-3 prostate cancer cells. The results showed that the properly substituted 1,4-dioxane nucleus proved to be a suitable scaffold for selective alpha 1D-AR antagonists (compound 14), potential anticancer agents (compound 13), and full 5-HT 1A receptor agonists (compound 15). In particular, compound 15 may represent a novel lead in the development of highly potent 5-HT 1A receptor full agonists useful as antidepressant and neuroprotective agents.
We have characterized the pharmacological antagonism, i.e., neutral antagonism or inverse agonism, displayed by a number of ␣-blockers at two ␣1-adrenergic receptor (AR) subtypes, ␣ 1a -and ␣ 1b -AR. Constitutively activating mutations were introduced into the ␣ 1a -AR at the position homologous to A293 of the ␣ 1b -AR where activating mutations were previously described. Twenty-four ␣-blockers differing in their chemical structures were initially tested for their effect on the agonistindependent inositol phosphate response mediated by the constitutively active A271E and A293E mutants expressed in COS-7 cells. A selected number of drugs also were tested for their effect on the small, but measurable spontaneous activity of the wild-type ␣ 1a -and ␣ 1b -AR expressed in COS-7 cells. The results of our study demonstrate that a large number of structurally different ␣-blockers display profound negative efficacy at both the ␣ 1a -and ␣ 1b -AR subtypes. For other drugs, the negative efficacy varied at the different constitutively active mutants. The most striking difference concerns a group of [4,5] decane-7,9-dione (REC 15/3039), REC 15/2739, and REC 15/3011, which are inverse agonists with profound negative efficacy at the wild-type ␣ 1b -AR, but not at the ␣ 1a -AR.Adrenergic receptors (ARs) mediate the functional effects of epinephrine and norepinephrine by coupling to several of the major signaling pathways modulated by guanine nucleotide regulatory proteins (G proteins). The AR family includes nine different gene products: three  (1, 2, 3), three ␣ 2 (␣2A, ␣2B, ␣2C), and three ␣1 (␣ 1a , ␣ 1b , ␣1d) receptor subtypes. Like all G protein-coupled receptors (GPCR), the ARs share seven hydrophobic regions that form a transmembrane ␣-helical bundle and are connected by alternating intracellular and extracellular hydrophilic loops. Mutational analysis of the ARs has revealed that the ␣-helical bundle contributes to form the ligand binding site of the receptor, whereas amino acid sequences of the intracellular regions appear to mediate the interaction of the receptor with G proteins as well as with different signaling and regulatory proteins (Wess, 1997).Both selective and nonselective antagonists for different AR subtypes are widely used in a variety of pathological conditions, including hypertension, heart failure, and prostate hypertrophy as well as in mental diseases such as depression. Several studies have demonstrated that -blockers can behave either as neutral antagonists or inverse agonists at the wild-type 2-AR or at a constitutively active 2-AR mutant (Samama et al., 1993b;Chidiac et al., 1994). However, inverse agonism at other AR subtypes has been less extensively investigated. It has been previously reported that a small range of ␣-blockers could inhibit the agonist-independent phospholipase C as well as phospholipase D responses mediated by constitutively active mutants of the ␣ 1b -AR (Lee et al., 1997). A recent study demonstrated that some ␣-blockers can inhibit the spontaneous activity ...
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