Structure-Based Drug Design of ADRA2A Antagonists Derived from Yohimbine

Yohimbine, a natural indole alkaloid and a nonselective
adrenoceptor
antagonist, possesses potential benefits in treating inflammatory
disorders and sepsis. Nevertheless, its broader clinical use faces
challenges due to its low receptor selectivity. A structure–activity
relationship study of novel yohimbine analogues identified amino esters
of yohimbic acid as potent and selective ADRA2A antagonists. Specifically,
amino ester 4n, in comparison to yohimbine, showed a
6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index.
Compound 4n also demonstrated high plasma and microsomal
stability, moderate-to-low membrane permeability determining its limited
ability to cross the blood–brain barrier, and negligible toxicity
on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study
the involvement of adrenoceptor subtypes in pathophysiologic conditions
such as inflammation and sepsis and a novel candidate for further
preclinical development to treat ADRA2A-mediated pathologies.