Small-Molecule Agonists and Antagonists of the Opioid Receptor-Like Receptor (ORL1, NOP): Ligand-Based Analysis of Structural Factors Influencing Intrinsic Activity at NOP

Abstract

A BSTRACTThe recently discovered fourth member of the opioid receptor family, the nociceptin receptor (NOP) and its endogenous ligand, the heptadecapeptide nociceptin, are involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of smallmolecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents a brief overview of the several recently reported NOP ligands, classifi ed as NOP agonists and antagonists, with an emphasis on the analysis of the structural features that may be important for modulating the agonist/antagonist profi le (intrinsic activity) of these ligands. Structure-activity relationships in our own series of dihydroindolinone-based NOP ligands and those of the various reported ligands indicate that the li pophilic substituent on the common basic nitrogen present in all NOP ligands plays a role in determining the agonist/antagonist profi le of the NOP ligand. This analysis provides a basis for the rational drug design of NOP ligands of desired intrinsic activity and provides a framework for developing pharmacophore models for high affi nity binding and intrinsic activity at the NOP receptor. Since NOP agonists and antagonists both have therapeutic value, rational approaches for obtaining both within a high-affi nity binding class of compounds are very useful for designing potent and selective NOP ligands with the desired profi le of intrinsic effi cacy.

The Pharmacology of Ro 64‐6198, a Systemically Active, Nonpeptide NOP Receptor (Opiate Receptor‐Like 1, ORL‐1) Agonist with Diverse Preclinical Therapeutic Activity

“…As hypothesized in the SAR studies (see preceding text), this hydrophobic region of the binding pocket in the classic opioid receptors does allow for larger hydrophobic substituents, due to the smaller size of the amino acids and the greater flexibility of the aliphatic residues. It has also been hypothesized, based on the structures of several agonists and antagonists of the NOP receptor, that the lipophilic moiety at the piperidine nitrogen of Ro 64‐6198 is also important in determining agonist activity, such that agonist responses are produced because this lipophilic moiety occupies a binding site in the receptor that is located near the protonated piperidine (Zaveri et al 2005).…”

Activities of mixed NOP and μ‐opioid receptor ligands

“…We have synthesized and characterized several series of NOP ligands, many of which possess modest selectivity for NOP receptors ( Zaveri et al , 2004 ). We have carried out structure–activity relationship studies in several of our series, and reported that small changes in the piperidine nitrogen substituent can modulate agonist–antagonist activities of the NOP ligands ( Zaveri et al , 2005 ). Several ligands in our small molecule series also possessed significant affinity at μ‐ and some at κ‐opioid receptors ( Zaveri et al , 2004 ).…”

Synthesis and Biological Activity of Small Peptides as NOP and Opioid Receptors’ Ligands

“…Development of selective and highly potent peptide and nonpeptide agonist and antagonist ligands is of great importance for the understanding of the physiological and pathological roles of N/OFQ-NOP receptor system, too. Among them are N/OFQ-related peptides (Ambo, Kohara, Kawano, & Sasaki, 2007;Guerrini, Calò, et al, 2000;Naydenova, Todorov, Mateeva, et al, 2010;Guerrini, Calò, Bigoni, Rizzi, Regoli, & Salvadori, 2001;, small peptides, identified by screening of peptide combinatorial libraries (Dooley, Chung, Shiller, & Houghten, 1993;Dooley et al, 1997), and nonpeptide ligands such as Ro 64-6198 and JTC-801 (Zaveri, 2003;Zaveri, Jiang, Olsen, Polgar, & Toll, 2005). The synthesis of new NOP receptor ligands with higher affinity and lower enzymatic degradation is a primary goal of many research teams.…”