Chemistry, pharmacology, and structure-activity relationships with a new type of imidazolines exerting a specific bradycardic action at a cardiac site

Abstract

The reaction of alkyl halides with 2-(arylimino)imidazolidines (I) leads to imidazoline derivatives II, in which the side chain is situated at the bridge nitrogen atom between the phenyl group and the imidazoline ring. The new imidazolines (II) exert a specific bradycardic action at a cardiac site. Syntheses and pharmacology are shown and structure-activity relationships discussed. The results reveal that the imidazoline derivatives (II) represent a class of compounds with a novel type of cardiac action.

Imidazoline Receptor System: The Past, the Present, and the Future

“…Nevertheless, a new idea germinated very rapidly-that is, to determine whether it was pharmacologically possible to distinguish the hypotensive effects from the unwanted side effects and to develop better tolerated centrally acting drugs for lowering blood pressure (i.e., having less or no sedative effect, the most common side effect of clonidine). During the 1970s to 1980s, numerous structural analogs of imidazolines were synthesized, both in pharmaceutical companies and in academic pharmacochemistry laboratories (Boudier et al, 1975;Hoefke et al, 1975;Rouot et al, 1976;Leclerc et al, 1980;Stähle et al, 1980). Most often, they were screened according to their ability to activate a 2 -adrenergic receptors, since the a 2 -adrenergic theory dictated the mechanism of the hypotensive action of imidazoline derivatives.…”

HCN Channels Modulators: The Need for Selectivity

“…Imidazolines, such as alinidine, are structural analogues of clonidine, but, at variance with the latter, have a substituent on the exocyclic nitrogen atom. Staehle et al reported the bradycardic activity of a series of analogues with general formula I, measured in vivo in spinal rats [111]; these results can be related to the interaction with the HCN4 isoform in the SAN, although in these conditions heart rate may be affected by several mechanisms, excluding those mediated by the CNS. It was found that a double substitution with halogen in the ortho positions of the phenyl ring was optimal, with R 1 being bromine and R 2 being bromine or chlorine, suggesting that in the bioactive conformation the guanidine moiety and the aromatic ring should not be coplanar.…”

Synthesis and reactivity of heterocyclic hydroxylamine-O-sulfonates

“…It is pertinent to note that in the case of amidine derivatives of type F, described by Beak et al as 'protomeric ambident nucleophiles' [39], heterocyclic amidines of type G called 1,3-dinucleophiles [40] and 2-aryliminoimidazolidines H [41,42], which directly refer to the structure of the heterocyclic hydroxylamine D, the electrophilic attack at the less basic sp 2 hybridized exocyclic nitrogen atom is also favored (Figure 8). Such a reaction course has been rationalized using the Curtin-Hammett principle [43,44], hard and soft acids and bases (HSAB) [45], or just steric hindrance [40].…”