Guanidine and 2-Aminoimidazoline Aromatic Derivatives as α₂-Adrenoceptor Antagonists, 1:  Toward New Antidepressants with Heteroatomic Linkers

Abstract

The efficient preparation and pharmacological characterization of different families of (bis)guanidine and (bis)2-aminoimidazoline derivatives (“twin” and “half” molecules) as potential α2-adrenoceptor antagonists for the treatment of depression is presented. The affinity toward the α2-adrenoceptor of all the compounds prepared was measured in vitro in human brain tissue. Additionally, the activity as agonist or antagonist of those compounds with a pK i larger than 7 was determined in functional [35S]GTPγS binding assays in human brain tissue. Finally, the activity of the most promising compounds was confirmed by means of in vivo microdialysis experiments in rats. Compounds 1, 2b, 3b, 12b, 13b, 17b, 18b, 22b, 25b, 26b, 28b, and 30 showed a good affinity toward the α2-ARs. In general, the 2-aminoimidazoline derivatives displayed higher affinities than their guanidine analogues. Finally and most importantly, compounds 18b and 26b showed antagonistic properties over α2-ARs not only in vitro [35S]GTPγS binding but also in vivo microdialysis experiments. Moreover, both compounds have shown to be able to cross the blood−brain barrier and, therefore, they can be considered as potential antidepressants.

Pyridin-2-yl Guanidine Derivatives: Conformational Control Induced by Intramolecular Hydrogen-Bonding Interactions

“…The 1 H NMR spectra of the majority of the N,N'-di-Boc protected phenylguanidine derivatives previously synthesised in our group 3,4,5 show the CH 3 protons of the tert-butyl groups as two separate signals integrating for nine protons each, suggesting the chemical inequivalence of the two N-Boc groups. This could be explained by the formation of two IMHBs involving the Boc carbonyl groups and guanidine hydrogens H1' and H4', which is supported by the deshielding recorded for these two protons' signals (>10 ppm).…”

“…During the last 10 years our group has been working on the synthesis 1 and biological evaluation of aromatic guanidine derivatives both as α-adrenoceptor ligands for the treatment of CNS disorders 2,3,4,5 and as DNA minor groove binders. 6,7 The biological importance of guanidines is highlighted by the prevalence of guanidine-carboxylate saltbridges in protein structures, a feature which is often closely linked to protein function .…”

New Bis(2-aminoimidazoline) and Bisguanidine DNA Minor Groove Binders with Potent in Vivo Antitrypanosomal and Antiplasmodial Activity

“…Rodriguez et al 18 The synthesis of 10a-b, 13b, 14a-b, 16a-b, 27a-b, 28a, 32a-b, 36a-b, 37b and their Boc-protected precurors will be reported elsewhere. 19 The Compounds 20a, 20b, 21a and 21b were studied as their trifluoroacetate salts (Scheme 1).…”

Microwave‐Assisted Cross‐Coupling for the Construction of Diaryl Sulfides

“…Aryl sulfides and their oxidized forms, sulfones and sulfoxides, are common functional groups in pharmaceutical agents such as nonsteroidal anti-inflammatory agents, 1 HIV protease inhibitors and antiviral agents, 2 selective M 2 muscarinic receptor antagonists, 3 leukocyte function-associated antigen-1/intracellular molecule-1 interaction antagonists, 4 leukotriene B 4 antagonists, 5 histone deacetylase inhibitors, 6 fatty acid amide hydrolase inhibitors, 7 a 2 -adrenoceptor antagonists, 8 and gonadotropin-releasing hormone antagonists. 9 Most importantly, diaryl sulfides serve as useful starting materials for the construction of heterocycles containing sulfur atom and precursors leading to sulfones and sulfoxides.…”