Zhengming Chen

DiPOA ([8-(3,3-Diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic Acid), a Novel, Systemically Available, and Peripherally Restricted Mu Opioid Agonist with Antihyperalgesic Activity: I. In Vitro Pharmacological Characterization and Pharmacokinetic Properties

Mu opioid receptors are present throughout the central and peripheral nervous systems. Peripheral inflammation causes an increase in mu receptor levels on peripheral terminals of primary afferent neurons. Recent studies indicate that activation of peripheral mu receptors produces antihyperalgesic effects in animals and humans. Here, we describe the in vitro pharmacological and in vivo pharmacokinetic properties of a novel, highly potent, and peripherally restricted mu opioid agonist, [8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid (DiPOA). In a radioligand binding assay, DiPOA inhibited [3H]-diprenorphine binding to recombinant human mu receptors with a Ki value of ∼0.8 nM. The rank order of affinity for DiPOA binding to recombinant human opioid receptors was mu > kappa ≈ ORL-1 >> delta. DiPOA showed potent agonist effects in a human mu receptor guanosine 5′-O-(3-[35S]thio)triphosphate functional assay, with an EC50 value of ∼33 nM and efficacy of ∼85% {normalized to the mu agonist, [d-Ala2,MePhe4,Gly(ol)5]enkephalin}. Low potency agonist activity was also seen at ORL-1 and kappa receptors. DiPOA bound competitively to the opioid binding site of human mu receptors as demonstrated by a parallel rightward shift in its concentration-response curve in the presence of increasing concentrations of naltrexone. High and sustained (≥5 h) plasma levels for DiPOA were achieved following intraperitoneal administration at 3 and 10 mg/kg; central nervous system penetration, however, was ≤4% of the plasma concentration, even at levels exceeding 1500 ng/ml. As such, DiPOA represents a systemically available, peripherally restricted small molecule mu opioid agonist that will aid in understanding the role played by mu opioid receptors in the periphery.

Design and parallel synthesis of piperidine libraries targeting the nociceptin (N/OFQ) receptor.

Based on literature structures, we proposed a pharmacophore for NOP receptor ligands and used it as a guide for the design of a focused piperidine library and an optimization library. Potent NOP receptor agonists and antagonists were obtained from these libraries as well as a few potent, mu selective agonists.