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

The discovery of the opioid receptor like-1 (ORL-1) receptor and of its end ogenous agonist nociceptin/orphanin FQ has attracted great interest in the scientific community giving rise, in the last five years, to a flurry of bi ological 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 d ocumented. However, a clear understanding of the potential therapeutic valu e associated with the modulation of the ORL-1 receptor needs the developmen t of selective non-peptide agonists and antagonists allowing systemic route s of administration. This review addresses the advances made by several res earch 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 selectiv e agonists and antagonists, such as Ro 64-6198, J-113397 and JTC-801. Effor ts 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.