Discovery of Selective Alpha_2C Adrenergic Receptor Agonists

Abstract

Something to ease the pain: Chemical modification of a 2‐amino‐oxazoline scaffold led to the identification of α2C adrenergic receptor (AR) agonists. These ligands were characterized by a dual α2C‐AR agonist/α2A‐AR antagonist profile. Structure–activity relationships were studied, and screening in anesthetized rats demonstrated a superior margin of safety for this class of compounds with respect to cardiovascular effects compared with nonselective α2‐AR agonists.

Advantageous safety profile of a dual selective alpha2C agonist/alpha2A antagonist antinociceptive agent

“…When comparing their binding and functional profile, both compounds had similar affinity for the a 2C -AR subtype, but opposite functional activity on the a 2A -AR subtype and on a 1 -AR. Moreover, compound A exhibited a lower affinity for a 2B -AR than clonidine in a binding assay using human recombinant receptor subtypes [14]. All together, these data support the lack of involvement of the a 2C -AR subtype in the peripheral vasoconstriction.…”

“…We explored the structure–activity relationships of several chemical scaffolds targeting the α 2C subtype. Compound A is a 2‐amino‐oxazoline derivative identified as a dual α 2C ‐AR agonist/α 2A ‐AR antagonist in in vitro‐binding and functional assays, exhibiting efficacy in classical pain models . To verify the safety advantages of this new concept, we assessed the cardiovascular and CNS effects of compound A in six different animal models, using clonidine as comparator.…”

“…Starting from our past knowledge of the α 2 ‐AR chemistry and pharmacology, which led to the discovery of mivazerol , a highly potent nonselective agonist, we explored the structure–activity relationship of several chemical scaffolds targeting the α 2C ‐AR subtype. Compound A ( Figure ) is a 2‐amino‐oxazoline derivative that was identified as a dual α 2C ‐AR agonist/α 2A ‐AR antagonist in in vitro‐binding and functional assays, exhibiting efficacy in classical pain models (mouse formalin test and rat chronic constriction injury model of neuropathic pain) .…”

A novel gabapentin analogue assuages neuropathic pain response in chronic sciatic nerve constriction model in rats

“…Moreover, drugs which are marketed for the management of neuropathic pain are less than optimal and mitigate pain in only about 50% of patients, so therapy of neuropathic pain is a notable unmet medical challenge [13,15]. At present, in the anticonvulsant drug category, GBP and pregabalin (PGB), are the most frequently prescribed [8,16,17] while the tricyclics are the those of choice among the antidepressants [14,[18][19][20].…”

The association of an alpha2C adrenoreceptor gene polymorphism with vasomotor symptoms in African American women

“…There has been limited demonstration of genetic polymorphisms associated with VMS. Notably, the ADRA2C del (322-325) adrenoreceptor is a deletion polymorphism that has been associated with an increased norepinephrine response to stress, 8 and appears to be an important regulator of autonomic activity. This deletion has also been associated with thermoregulation.…”