Nociceptin

FIGURE 17.12 Rigidifying of nociceptine ligands J-1 and J-2 after computational determination of a low energy scaffold SR14136 is equipo-tent to J-2, a pharmacophore can be adjusted. Source Adapted with modifications firom Ref. [42] 

The discovery of the potent HCV inhibitors 14 and 16 resulted mainly from conformational rigidiflcation, a gain of entropy is probably responsible for the affinity increase (cpd 8 to cpd 14) of about a factor 50 (8kJ/mol). The identification of compound 17 follows a classical step when an ortho-effect (binding increase with an ortho-substituent) is identified the design is conducted so as to find the optimum dihedral angle. 

---

Nociceptin and orphanin are synonyms for the peptide that acts at an opioid-like receptor. Nociceptin may act by inhibiting tachykinin release from sensory C-fibres, and a clinical trial has started to test its effects on cough. 

Nociceptin is an opioid peptide, which is the endogenous ligand for the opioid receptor-like protein (ORL). 

Prototypic ligands Morphine Met/leu-enkephalin Ethylketocyclacozine Nociceptin/OFQ... 

The four opioid receptors display in vivo binding preference for mu-endorphins and endomorphins, delta-enkephalins, kappa-dynorphin and ORLl-nociceptin/orphanin FQ (Table 12.2). 

The opioid receptors are for the endogenous opioids, peptide transmitters, jS-endorphin, endomorphins, enkephalins, dynorphins and nociceptin. Thus all the problems of drugs based on peptides need to be overcome in order for the roles of these... 

Endogenous opioid /i-endorphin Endomorphins Enkephalins Dynorphins Nociceptin... 

Compound 24 represents a series of potent spiropiperidine GlyT-1 inhibitors that showed significant binding to the p opioid and nociceptin/ orphanin FQ peptide (NOP) receptors [67]. The hydroxy analog 25 demonstrated improved selectivity and N-propyl analog 26 exhibited increased microsomal stability but reduced GlyT-1 potency (EC50 = 450 nM) [68]. 

The method appears to be particularly suitable for the study of expensive compounds and/or species available in very low amounts. Figure 10.19 shows the application of IM to the study of the adsorption equilibria of a polypeptide, nociceptin/orphanin FQ, on a C,g column [40]. Isotherms (Figure 10.20) were obtained by numerical procedure through the fitting of the overloaded band profiles obtained under different conditions. Adsorption data allowed for the prediction of the band profile under overloaded gradient conditions (Figure 10.21) with a minimal amount of compound consumption. 

FIGURE 10.19 Comparison between empirical profiles (points) and peaks obtained via IM (lines) when a Langmuir adsorption isotherm is assnmed. Mobile phase ACN 16% (v/v) in aqueons TFA 0.1% (v/v) mixture nociceptin-injected concentrations 5.0, 2.7, and 1.3 g/L. (Reprinted from Marchetti, N. et al., J. Chromatogr. A, 1079, 162, 2005. With permission from Elsevier.)... 

Next to these three classical receptor families a additional opioid receptor has been identified. This receptor is known as the nociceptin receptor or ORL 1 receptor. Its natural ligand is known... 

Darland T et al. Orphanin FQ/nociceptin A role in pain and analgesia, but so much more. 

Moran TD et al. Cellular neurophysiological actions of nociceptin/orphanin FQ. Peptides 2000 21 969-976. 

Figure 7.1 Amino acid structure of nociceptin/Orphanin FQ.

---