Abstract |
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., a cluster of cardiovascular ( hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over α2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I1imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome.
|
Authors | Vincent Gasparik, Hugues Greney, Stephan Schann, Josiane Feldman, Lyne Fellmann, Jean-Daniel Ehrhardt, Pascal Bousquet |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 58
Issue 2
Pg. 878-87
(Jan 22 2015)
ISSN: 1520-4804 [Electronic] United States |
PMID | 25521963
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antihypertensive Agents
- Imidazoline Receptors
- Ligands
- Pyrrolidines
- Sympatholytics
- imidazoline I1 receptors
|
Topics |
- Animals
- Antihypertensive Agents
(chemical synthesis, pharmacology)
- Blood Pressure
(drug effects)
- Blood-Brain Barrier
- Drug Discovery
- Heart Rate
(drug effects)
- Imidazoline Receptors
(metabolism)
- Ligands
- Metabolic Syndrome
(drug therapy)
- Pyrrolidines
(chemical synthesis, pharmacology)
- Rats
- Rats, Wistar
- Structure-Activity Relationship
- Sympatholytics
(chemical synthesis, pharmacology)
|