Nociceptin/Orphanin FQ and Urinary Bladder

Biased Agonism at Nociceptin/Orphanin FQ Receptors: A Structure Activity Study on N/OFQ(1–13)-NH2

“…The peptide nociceptin/orphanin FQ (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln, N/OFQ) is the endogenous ligand of the Gi coupled N/OFQ peptide (NOP) receptor. , Previous structure–activity relationship studies, that have been recently reviewed, suggested that the N/OFQ N-terminal message domain (Phe-Gly-Gly-Phe) binds the NOP binding pocket while the address domain of the peptide (Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln) interacts with the second extracellular loop of the receptor. This proposal has been confirmed by the available NOP crystal structure studies. , The N/OFQ-NOP receptor system regulates several biological functions, including locomotor activity, memory, emotional states, food intake, drug abuse, pain transmission, micturition, cough reflexes, and cardiovascular, respiratory, and immune functions. , Thus, the NOP receptor is an attractive target for the development of innovative drugs, and there is now clinical evidence for possible indications of NOP ligands, including systolic hypertension for the partial agonist SER100, urinary incontinence due to overactive bladder for the full agonists N/OFQ and Rec 0438, pain for the mixed NOP/opioid receptor agonist cebranopadol, and depression for the antagonist BTRX-246040 …”

“…4,5 The N/OFQ-NOP receptor system regulates several biological functions, including locomotor activity, memory, emotional states, food intake, drug abuse, pain transmission, micturition, cough reflexes, and cardiovascular, respiratory, and immune functions. 1,2 Thus, the NOP receptor is an attractive target for the development of innovative drugs, and there is now clinical evidence for possible indications of NOP ligands, including systolic hypertension for the partial agonist SER100, 6 urinary incontinence due to overactive bladder for the full agonists N/OFQ and Rec 0438, 7 pain for the mixed NOP/opioid receptor agonist cebranopadol, 8 and depression for the antagonist BTRX-246040. 9 However, the pleiotropic effects exerted by N/OFQ and NOP agonists may be viewed as an obstacle in terms of drug development.…”

Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040

“…Through the activation of the NOP receptor N/OFQ regulates different biological functions and pathological states (Lambert, 2008). NOP receptor agonists are now under clinical development for the treatment of hypertension (Kantola et al, 2017), urinary incontinence (Angelico et al, 2019) and pain (Calo and Lambert, 2018;Tzschentke et al, 2019). Several chemically diverse NOP antagonists have been described in the literature including the peptides [Nphe 1 ]N/OFQ(1-13)-NH2 (Calo et al, 2000) and UFP-101 (Calo et al, 2002), and the small molecules J-113397 (Ozaki et al, 2000), SB-612111 (Zaratin et al, 2004), and Comp 24 (Goto et al, 2006) (for a review see (Toll et al, 2016;Zaveri and Meyer, 2019)).…”

Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance

“…The broad spectrum of actions of N/OFQ has provoked the interest of academic and industrial researchers and generated a large panel of N/OFQ receptor ligands useful for target validation studies. In fact, N/OFQ receptor agonists have been proposed as innovative drugs for treating hypertension [ 250 ] and urinary incontinence [ 251 ], whereas N/OFQ receptor selective antagonists have been suggested as novel treatment for Parkinson’s disease [ 252 ], depression (including BTRX-246040, an NOP antagonist already tested in humans) [ 253 , 254 ], and possible drug abuse [ 239 ]. BTRX-246040 was also found to reduce depression symptoms in a second trial with heavy alcohol drinkers.…”