Transfer of SAR information from hypotensive indazole to indole derivatives acting at α-adrenergic receptors: In vitro and in vivo studies

1‐[(Imidazolidin‐2‐yl)imino]‐1H‐indoles as new hypotensive agents: synthesis and in vitro and in vivo biological studies

“…Similar hemodynamic activity profile of marsanidine‐like compounds D and indole derivatives 3 suggests that the hypotensive effect of indoles 3 is mediated by central α 2 ‐ARs. In contradistinction to our earlier observation that the bioisosteric 1‐[(imidazolin‐2‐yl)methyl]indazoles ( B ) and 1‐[(imidazolin‐2‐yl)methyl]indoles ( C ) exert different hemodynamic effects, the present studies indicate that 1‐[(imidazolidin‐2‐yl)imino]indazoles ( D ) and their indole analogues 3 produce similar cardiovascular effects. Moreover, the results of in vitro metabolic stability studies as well as in silico model revealed that indoles 3 are not vulnerable to rapid first‐phase oxidative metabolism.…”

“…Recently, our SAR studies of imidazoline‐containing α‐adrenergic agents showed that the isosteric replacement of the indazole ring in 1‐[(imidazolin‐2‐yl)methyl]indazoles B by the indole moiety led to compounds C (Figure ), which exert different functional properties with respect to α‐ARs. Indeed, imidazoline‐containing indazoles B exhibited hypotensive properties due to α 1 ‐AR antagonist activity, while their indole analogues C were described as partial α 2A ‐AR agonists showing clonidine‐like cardiovascular pattern . Furthermore, we described 1‐[(imidazolidin‐2‐yl)imino]‐1 H ‐indazoles D (Figure ; marsanidine‐like ligands), which proved to be hypotensive α 2 ‐AR agonists .…”

Adrenergic Modulation With Photochromic Ligands

“…We thus designed a set of putative photoswitchable adrenergic ligands, named "adrenoswitches", by replacing the two-atom linker with an azo group while constraining the cyclic amidine moiety to the closest structurally related aromatic derivatives. Since small structural changes can drastically alter the pharmacological profile of the molecules [8][9][10][11] , we opted for a classical medicinal chemistry approach maintaining unvaried the substituted benzene moiety while exploring different heterocycles in order to afford both adrenergic activity and photochromism. The ortho-dichlorobenzene system common to clonidine and lofexidine seemed a feature worth maintaining for both purposes.…”

Preventing delirium: beyond dexmedetomidine – Authors' reply

“…Furthermore, in agreement with Avramescu and colleagues, it is crucial that analogues of dexmedetomidine or its derivatives with fewer side-effects are developed; a goal that has not yet been achieved. 4 Notably, dexmedetomidine use is recommended in highly monitored settings because of its potential side-effects on the respiratory and circulatory systems. Determination of the efficacy and safety of dexmedetomidine in other patient populations, such as those in the palliative care centres or nursing homes, is urgently needed.…”