Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome.

New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs α2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e.

Methylation of imidazoline related compounds leads to loss of α₂-adrenoceptor affinity. Synthesis and biological evaluation of selective I₁ imidazoline receptor ligands.

Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration.

Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

Background: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity.

The central hypotensive effect induced by alpha 2-adrenergic receptor stimulation is dependent on endothelial nitric oxide synthase.

Objective: The aim of the present study was to determine whether the central antihypertensive effect of drugs that act via central alpha 2-adrenergic receptors is mediated by the nitric oxide-ergic system.

Methods: The hypotensive effects of dexmedetomidine, a 'pure' alpha2-adrenergic agonist, were compared in endothelial nitric oxide synthase knockout and wild-type control mice.

Results: When injected intravenously (5 mug/kg) in wild-type mice, dexmedetomidine elicited a depressor response (60 +/- 4 to 34 +/- 1 mmHg, P < 0.

G-protein inwardly rectifying potassium channels are involved in the hypotensive effect of I1-imidazoline receptor selective ligands.

Objective: The present study examined the role of G-protein inwardly rectifying potassium (GIRK) channels in the depressor responses elicited by intracisternal injections of imidazoline-like drugs in anesthetized rabbits.

Methods And Results: Intracisternal injections of the I1-imidazoline receptor (I1R) selective ligands LNP509 (30 microg/kg) and LNP640 (2 microg/kg) (subthreshold doses), and of the GIRK channel opener flupirtine (30 microg/kg) did not affect mean arterial blood pressure (MAP). LNP509 and LNP640, however, elicited substantial depressor responses in rabbits pretreated with flupirtine (-17 +/- 2 and -18 +/- 1 mmHg, respectively, P < 0.

Opposite to alpha2-adrenergic agonists, an imidazoline I1 selective compound does not influence reflex bradycardia in rabbits.

This work aimed to study the respective effects of central alpha2-adrenergic receptors (alpha2-ARS) and I1 imidazoline receptors (I1Rs) in the facilitatory effects of imidazoline-like drugs on the reflex bradycardia (RB). Experiments were performed in anaesthetized rabbits. The reflex bradycardic response was induced by phenylephrine injected i.

Imidazoline binding sites (IBS) profile modulation: key role of the bridge in determining I1-IBS or I2-IBS selectivity within a series of 2-phenoxymethylimidazoline analogues.

The alpha- and beta-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and the corresponding enantiomers were prepared and tested with the purpose of studying the role played by the ethylene bridge in modulating I(1)- and I(2)-IBS selectivity. The alpha-methylation appeared to be extremely critical regarding the affinity and selectivity for the I1-IBS subtypes (I1/I2 = 186 for imidazoline 7) and the stereospecificity of interaction (eudismic ratio (S)-(-)-7/(R)-(+)-7 = 5888). Instead, even if in a more limited fashion, the -methylation tended toward I2-IBS selectivity (I2/I1 = 50 for imidazoline 8).

Nitric oxide discriminates the sites and mechanisms of action of centrally acting anti-hypertensive drugs in rabbits.

The aim of the present study was to further investigate the mechanisms of the central hypotensive action of catecholamines and imidazolines, in particular the role of nitric oxide (NO). Microinjections into the nucleus reticularis lateralis (NRL/RVLM) located in the rostroventrolateral part of the medulla (RVLM) and/or into the nucleus tractus solitarii (NTS) were performed in pentobarbital-anesthetized rabbits. Microinjections of brimonidine (1 ng/kg), which binds both alpha(2)-adrenergic receptors (alpha(2)-ARs) and I(1) imidazoline receptors (I(1)Rs), into the NRL/RVLM induced hypotension (69+/-2 vs.

First model of spontaneous vagal hyperreactivity and its mode of genetic transmission.

Background: The main purpose of our study was to define an animal model of vagal hyperreactivity and its genetic transmission.

Methods And Results: We first investigated the vagal reactivity with phenylephrine in conscious rabbits. Barosensitivity and the maximal bradycardic response were measured at the upper mean blood pressure plateau.

Evidence for synergy between alpha(2)-adrenergic and nonadrenergic mechanisms in central blood pressure regulation.

Background: Both alpha(2)-adrenergic and non--alpha(2)-adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP).

Methods And Results: LNP 509, which appeared in this study to be devoid of alpha(2A)-adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively.