2. Pharmacological characterization of two NOP receptor antagonists,
2.4. SB-612111 is devoid of intrinsic activity
SB-612111 did not exhibit any agonistic activity in our preparations at the concentration up to 1 μM. This is in line with previous reports in the culture cells, peripheral preparations and mouse cortical synaptosomes (Spagnolo et al., 2007). This characteristic of SB-612111, a pure NOP receptor antagonist without intrinsic activity, makes it valuable in elucidating the functional roles of endogenous N/OFQ in vivo
(Khroyan et al., 2009; Rizzi et al., 2007; Zaratin et al., 2004).
2.5. SB-612111 displays highly selectivity for NOP receptors.
In the present study, we also verified the selectivity of SB-612111 for NOP receptors in brain tissue preparations. In vlPAG neurons, activation of μ-opioid receptors, but not κ- or δ-opioid receptors, also results in membrane hyperpolarization by activation of GIRK channels (Chieng and Christie, 1994). Therefore, κ-opioid and δ-opioid receptors are unlikely the targets mediating GIRK channel activation.
Furthermore, SB-612111 did not affect the GIRK current activated by DAMGO, a μ-opioid receptor selective agonist. Therefore, it is reasonably to conclude that the antagonism of SB-612111 is selective for NOP receptors among the opioid receptors in the vlPAG. This result extends previous findings that SB-612111 neither displayed any activity at recombinant μ-opioid receptors (Zaratin et al., 2004) and nor affected morphine-induced antinociception in the tail-flick assay (Khroyan et al., 2009).
2.6. Development of NOP receptor antagonists.
Several peptide and non-peptide NOP receptor antagonists have been developed since 1998. The characteristic of susceptible to peptidase hydrolysis in peptide antagonists limits their in vivo applications. Early developed non-peptide antagonists are
flawed by their non-specificity or by their residual agonist activity (Chiou et al., 2007).
J-113397 was developed as a very potent and selective antagonist of NOP receptors without intrinsic activity (Chiou and Fan, 2002; Ozaki et al., 2000b). However, it was later found to have psychomimetic central activity (Koizumi et al., 2004) which is likely attributed to its affinity at σ receptors (Chiou et al., 2007). UFP-101 has widely determined as an ideal NOP receptor antagonist in a series of in vitro and in vivo studies (Calo' et al., 2005). Compound 24 has the merit of being a non-peptide NOP receptor antagonist and devoid of intrinsic activity. However, its non-specificity at higher concentrations might limit its usefulness in the studies investigating the functional roles of endogenous of N/OFQ. On the other hand, SB-612111, with the merits of non-peptide nature, good potency, specificity and devoid of intrinsic activity, is useful NOP receptor antagonist in investigating the physiological or pathological roles of endogenous N/OFQ. Currently, SB-612111 amd Compound 24 (product name is BAN ORL 24) are availableat Tocris Bioscience.
Conclusion
It is concluded that in vlPAG neurons, functional heterogeneity of NOP receptors can be revealed by Ro 64-6198 and (+)-5a Compound, but not by [Tyr10]N/OFQ(1-11) or NOP receptor antagonsits. (+)-5a Compound affects the same subset of NOP receptors as Ro 64-6198 effects in vlPAG neurons. These neurons are mostly GABAergic and morphologically distinct from the (+)-5a Compound-insensitive ones.
[Tyr10]N/OFQ(1-11) precluded the effect of N/OFQ, suggesting it affects all N/OFQ-sensitive NOP receptors. Thus, the functions of different binding sites of N/OFQ in rodent brain remain to be clarified. Although neither Compound 24, nor SB-612111 can differentiate NOP receptor subsets in vlPAG neurons, we have proven Compound 24 is a competitive antagonist of NOP receptors with moderate potency and selectivity, but SB-612111 is a pure, potent and selective antagonist of NOP receptors.
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