Development of nociceptin receptor (NOP) agonists and antagonists

Abstract

The nociceptin opioid (NOP) receptor is the most recently discovered member of the family of the opioid receptors; its endogenous agonist is the peptide nociceptin. Due to the subsequent elucidation of its physiological role in both central and peripheral nervous system and in some non-neural tissues, there is a rapidly growing interest in the pharmacological application of substances active on this receptor. Despite the current clinical use of a morphinane-based NOP/MOP mixed ligand (buprenorphine) as an analgesic and in the treatment of drug addictions, so far just a few clinical trials have been made with selective NOP ligands. However, the perspective of their utilization is rapidly growing. Agonists can find applications in the treatment of neuropathic pain, anxiety, cough, drug addition, urinary incontinence, anorexia, congestive heart failure, hypertension; and antagonists for pain, depression, Parkinson's disease, obesity, and as memory enhancers. Besides peptide ligands, which are still subjected to many pharmacological investigations, many different chemical classes of NOP ligands have been discovered: piperidines, nortropanes, spiropiperidines, 4-amino-quinolines and quinazolines, and others. The new advances in establishing structure-activity relationships, also with the help of modeling studies, can permit the development of more active and selective molecules.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…In the frame of research activities mainly performed in industrial laboratories several different chemical classes of small molecule NOP ligands were discovered including piperidines, spiropiperidines, nortropanes, 4-amino-quinolines, quinazolines, and others. A detailed medicinal chemistry analysis of most if not all the available NOP ligands was recently published (Mustazza and Bastanzio, 2011). This section describes and discusses the pharmacological features of NOP-selective ligands including peptide and nonpeptide compounds that have been most important to the field, particularly with respect to their involvement in pain and drug abuse, thereby leading to a better understanding of the role of the NOP receptor system in these processes.…”

“…These have been NOP Receptor Biology and Function analyzed in detail in recent reviews (Mustazza and Bastanzio, 2011;Calo' and Guerrini, 2013). In the following paragraphs we briefly summarize those studies leading to the identification of chemical modifications of the N/OFQ sequence able to increase binding affinity or to modulate agonist efficacy and therefore instrumental in generating useful pharmacological tools.…”

Bifunctional Peptide-Based Opioid Agonist–Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain

“…16,17 The nociceptin/orphanin FQ system seems to be involved in the modulation of acute nociceptive stimulation, as well as in chronic pain processes, for example, in inflammation 18,19 and neuropathic pain. 20–23 It is well established that N/OFQ may perform both pro- and antinociceptive actions, depending on the administration route 24 or dosage, 25 and both agonists and antagonists of NOP appear to be useful. 16,24,26 …”

“…20–23 It is well established that N/OFQ may perform both pro- and antinociceptive actions, depending on the administration route 24 or dosage, 25 and both agonists and antagonists of NOP appear to be useful. 16,24,26 …”

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

“…Moreover, NOP is expressed in the peripheral nervous system as well as in the gastrointestinal tract, smooth muscles, and in cells of the immune system. Initially, N/OFQ was found to produce hyperalgesia, leading to the naming the peptide nociceptin (Meunier et al, 1995); however, in addition to pain, N/OFQ modulates other CNS behaviors, including stress and anxiety, depression, substance abuse, prolactin secretion, locomotor activity, body temperature, memory, and feeding (Mustazza and Bastanzio, 2011;Gavioli and Calo', 2013;Singh et al, 2013;Witkin et al, 2014).…”