ANALOGUES OF ALPHA1-ADRENOCEPTOR ANTAGONIST WB4101: DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION

The alpha-1-adrenoceptors (alpha-1-AR) are members of the G protein-coupled receptor family. To date, they have been classified into alpha-1A, alpha-1B and alpha-1D subtypes and the corresponding cloned counterparts alpha-1a, alpha-1b and alpha-1d.2,3 The design of agents selective for each of these three receptor subtypes is a challenge for medicinal chemists due to the therapeutic potential of selective alpha-1A and alpha-1D antagonists 4. Indeed, it has been claimed that alpha-1A-AR antagonists can be useful in the treatment of patients suffering benign prostatic hyperplasia 5,6,7 as well as alpha-1D-AR antagonists in relieving the irritative symptoms of this disease 8. Thus, an useful pharmacological agent might be an alpha-1-AR antagonist which is selective for the alpha-1A over the alpha-1B subtype and also endowed with activity at alpha-1D-AR such as to provide some potential additional therapeutic benefit 9. Historically, the first alpha-1A antagonist to be identified was WB4101, 10 a 2-aminomethyl-1,4-benzodioxane derivative, which was later found to be slightly selective for alpha-1A- and alpha-1D-ARs with respect to alpha-1B-AR and 5-HT1A serotoninergic receptor.5,11 On these bases we have undertaken a study on compounds structurally related to WB4101 aimed at identifying high affinity ligands for alpha-1A-AR with more pronounced selectivity over the other alpha-1-AR subtypes and 5-HT1A.12 The following design approaches have been done: 1. replacement of benzodioxane by a naphthodioxane or a tetrahydronaphthodioxane; 2. replacement of both benzodioxane and 2,6-dimethoxyphenyl by a tetrahydronaphthodioxane and ortho methoxy substituted 1-naphthyl respectively; 3. replacement of 2,6-dimethoxyphenyl by ortho substituted methoxy tetrahydronaphthyl or by unsubstituted naphtyl or ortho methoxy substituted 1- or 2- naphtyl; 4. replacement of 2,6-dimethoxyphenyl by 4-, 5- or 6-phenyl-2-methoxyphenyl system; Of all compounds, including WB4101, both the enantiomers have been synthesized and “in vitro” tested by binding and functional assays. The results which will be shown are relevant for the development of new WB4101-related compounds high affinity and specificity for 1A- and 1D-ARs. Bolchi, C. ; Catalano, P.; Fumagalli, L. Bioorg. Med. Chem. 2004, 12, 4937-4951 (a) Ford, A. P. D. W.; Williams, T. J.; Blue, D. R.; Clarke, D. E. Trends Pharmacol. Sci. 1994, 15, 167. (b) Hieble, J. P.; Bylund, D. B.; Clarke, A. E.; Eikenberg, D. C.; Langer, S. Z.; Lefkowitz, R. J.; Minneman, K. P.; Ruffolo, R. R. Jr. Pharmacol. Rev. 1995, 47, 266. (c) Hieble, J. P.; Ruffolo, R. R., Jr. Prog. Drug Res. 1996, 47, 81. Faure, C.; Pimoule, C.; Arbilla, S.; Langer, S. Z.; Graham, D. Eur. J. Pharmacol. Mol. Pharmacol. 1994, 15, 167. Malloy, B. J.;Price, D.T.; Price, R. R.; Bienstock, a. M.; Dole, M. K.; Funk, B. L.; Rudner, X. L.; Richardson, C. D.; Donatucci, C. F.; Schwinn, D. A. J. Urol. 1998, 160, 937. Kenny, B.; Ballard, S.; Blagg, J.; Fox, D. J. Med. Chem.1997, 40, 1293-1315. 6 Lepor, H.; Urol. Clin. N. Am.1995, 22, 375-386. Chapple, C. R. Br. J. Urol.1995, 76 (Suppl. 1), 47-55. Broten, T.; Scott, A.; Siegl, P. K. S. FASEB J 1998, 12, A445. Meyer, M. D.; Altenbach, R. J.; Basha, F. Z. J. Med. Chem. 2000, 43, 1586-1603. Nelson W. L.; Wennerstrom J. E.; Dyer D. C.; J. Med. Chem. 1977, 20, 880-885. Bolognesi, M. L., Budriesi, R., Cavalli, A., Chiarini, A. J.Med.Chem. 1999, 42, 4214-4224. L. Fumagalli, C. Bolchi, S. Colleoni Bioorg. Med. Chem 2005 13, 2547-2559.