1,4-Dioxane ring as a promising template of novel 5-HT1A full agonists

Among the large number of serotoninergic receptors the 5-HT1A subtype has grown into a considerable research due to its involvement in psychiatric disorders. 5-HT1A Agonists may be useful antidepressant [1] and neuroprotective agents [2]. Since the limited clinical efficacy of partial agonists, such as buspirone, the first 5-HT1A agent launched in the market, seems to be related to their low level of intrinsic activity [3], the discovery of 5-HT1A full agonists proves to be determinant. In the present study the α1-adrenoreceptor (α1-AR) antagonist WB 4101 was chosen as lead molecule because it is well known that this and related compounds are effective ligands also for 5-HT1A serotoninergic receptor and a high degree of homology exists between these two receptor families [4]. The quite planar 1,4-benzodioxane template of WB 4101 was replaced by the less conformationally constrained 1,4-dioxane ring substituted in its positions 5 or 6 with one or two pendant phenyl rings (compounds 1-12). The use of 1,4-dioxane was encouraged by a recent study of ours in which this nucleus demonstrated its bioversatility proving to be a suitable scaffold for efficacious and selective muscarinic agonists [5]. All compounds were tested at 5-HT1A receptors expressed in HeLa cells, and human cloned α1-AR subtypes, expressed in Chinese Hamster Ovary (CHO) cells. Compounds 2b, 5b, and 10-12 selected on the basis of their highest 5-HT1A affinity values (8.4-9.2), were examined in the [35S]GTPγS at the human cloned 5-HT1A receptors. The most interesting compound was 12 behaving as a potent full agonist with pD2 value (8.28; % max 106.3) significantly higher than that of 5-hydroxytryptamine. It also showed a good selectivity for 5-HT1A towards the α1A-, α1B- and α1D-AR subtypes (binding assays: 251.2, 251.2 and 50.1; functional assays: 37.2, 109.6, and 11.5, respectively). Therefore, it represents a new lead for developing potent full 5-HT1A agonists significantly selective over α1-ARs. [1] Blier, P.; Bergeron, R.; de Montigny, C. Neuropsychopharmacology 1997, 16, 333-338. [2] Torup, L.; Møller, A.; Sager, T. N.; Diemer, N. H. Eur. J. Pharmacol. 2000, 395, 137-141. [3] Glennon, R. A.; Malgorzata, D. Serotonin 1997, 2, 351-372. [4] Trumpp-Kallmeyer, S.; Hoflack, J.; Bruinvels, A.; Hibert, M. J. Med. Chem. 1992, 35, 3448-3462. [5] Piergentili, A.; Quaglia, W.; Giannella, M.; Del Bello, F.; Bruni, B.; Buccioni, M.; Carrieri, A.; Ciattini, S. Bioorg Med Chem. 2007, 15, 886-896