Lead generation and lead optimisation approaches in the discovery of selective, non-peptide ORL-1 receptor agonists and antagonists

TLDR

The opioid receptor‑like‑1 (ORL‑1) receptor and its endogenous agonist nociceptin/orphanin FQ have attracted intense research interest, with studies linking the receptor to antinociception, learning, memory, feeding, and anxiety, yet selective non‑peptide modulators are needed to clarify its therapeutic potential. The review surveys advances in discovering selective non‑peptide ORL‑1 receptor agonists and antagonists and examines medicinal chemistry strategies that evolved from early non‑selective ligands to potent selective compounds. The authors describe medicinal chemistry approaches that transformed initial non‑selective ligands such as NalBzoH and lofentanil into highly potent, selective agonists and antagonists like Ro 64‑6198, J‑113397, and JTC‑801. The newly developed non‑peptide tools have been pharmacologically characterized, advancing understanding of ORL‑1 receptor involvement in various pathophysiological conditions.

Abstract

The discovery of the opioid receptor like-1 (ORL-1) receptor and of its endogenous agonist nociceptin/orphanin FQ has attracted great interest in the scientific community giving rise, in the last five years, to a flurry of biological studies aimed at elucidating the role of this new receptor. Hence, the involvement of the ORL-1 receptor in many important processes, such as antinociception, learning and memory, feeding and anxiety, has been well documented. However, a clear understanding of the potential therapeutic value associated with the modulation of the ORL-1 receptor needs the development of selective non-peptide agonists and antagonists allowing systemic routes of administration. This review addresses the advances made by several research groups in the discovery of such compounds and discusses the medicinal chemistry strategies which, starting from the first non-selective ligands NalBzoH and lofentanil, led to the disclosure of highly potent and selective agonists and antagonists, such as Ro 64-6198, J-113397 and JTC-801. Efforts have also focussed on the pharmacological characterisation of the newly discovered non-peptide tools, which represent a significant step forward in the understanding of the involvement of the ORL-1 receptor in a number of possible pathophysiological conditions.