Guanidine and 2-Aminoimidazoline Aromatic Derivatives as α₂-Adrenoceptor Ligands: Searching for Structure−Activity Relationships

Abstract

In this paper, we report the synthesis of three new 2-aminoimidazoline (compounds 4b, 5b, and 6b) and three new guanidine derivatives (compounds 7b, 8b, and 9b) as potential alpha(2)-adrenoceptor antagonists for the treatment of depression. Their pharmacological profile was evaluated in vitro in human brain tissue and compared to the potential antidepressant 1 and the agonists 2 and 3. All new substrates were evaluated by in vitro functional [(35)S]GTPgammaS binding assays in human prefrontal cortex to determine their agonistic or antagonistic activity. Compound 8b was found to be an antagonist in vitro and was subjected to in vivo microdialysis experiments in rats. Moreover, a new synthesis of the precursor amines for compounds 4b-9b is presented.

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

“…19 The Compounds 20a, 20b, 21a and 21b were studied as their trifluoroacetate salts (Scheme 1). In the case of the thiourea derivatives 8d, 21d and 21e, an alternative strategy was employed to avoid the competitive reaction occurring between the thiourea linker of the starting material (i.e., 8 and 21) and the thiourea guanidine precursors for the HgCl 2 catalyst (Scheme 1).…”

On the protonated state of amidinium-like diaromatic derivatives: X-ray and UV studies

“…Compounds containing amidine-like groups (guanidines, 2-aminoimidazolines, isoureas) have shown to be active in different biological systems from binding to DNA [1][2][3] to inhibiting adrenergic receptors in the brain [4][5][6]. The protonation state of these amidine-like groups at physiological level plays a fundamental role in the interactions established with the target (hydrogen bonds, ionic contacts) and for this reason, information about this protonation state is crucial for the design of new biologically active derivatives.…”