Synthesis and Pharmacological Evaluation of 5-Pyrrolidinylquinoxalines as a Novel Class of Peripherally Restricted κ-Opioid Receptor Agonists

5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted kappa-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine kappa pharmacophore allows the fine-tuning of the pharmacodynamic and pharmacokinetic properties. The perhydroquinoxalines were synthesized stereoselectively using the concept of late stage diversification of the central building blocks 14. In addition to high kappa-opioid receptor affinity they demonstrate high selectivity over mu, delta, sigma(1), sigma(2), and NMDA receptors. In the [S-35]GTP gamma S assay full agonism was observed. Because of their high polarity, the secondary amines 14a (log D-7.4 = 0.26) and 14b (log D-7.4 = 0.21) did not penetrate an artificial blood-brain barrier. 14b was able to inhibit the spontaneous pain reaction after rectal mustard oil application to mice (ED50 = 2.35 mg/kg). This analgesic effect is attributed to activation of peripherally located kappa receptors, since 14b did not affect centrally mediated referred allodynia and hyperalgesia.