McLean Hospital, Belmont, Massachusetts, United States of America ; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America ; School of Chemistry and Bio21 Institute, University of Melbourne, Parkville, Australia.
PLoS One. 2013 Aug 14;8(8):e70701. doi: 10.1371/journal.pone.0070701. eCollection 2013.
Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets.
In binding assays, the three antagonists showed no detectable affinity (K(i)≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α(2C)-adrenoceptor (K(i) = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α(1A)-adrenoceptor (EC₅₀ = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M₁ receptor antagonist (K(B) = 3.7 µM). JDTic bound to the noradrenaline transporter (K(i) = 54 nM), but only weakly inhibited transport (IC₅₀ = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (K(i) = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers.
Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α(1A)-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists.
Nor-BNI、GNTI 和 JDTic 诱导选择性 κ 阿片受体拮抗作用，这种拮抗作用延迟且极其持久，但其他一些作用则起效迅速且持续时间短暂。这些化合物的瞬时作用不同，表明其中一些可能由其他靶点介导。
在结合测定中，三种拮抗剂对大多数非阿片受体和转运体（43 种测试中的 26 种）均无检测到的亲和力（K(i)≥10 μM）。没有一种非阿片类药物靶点对所有三种化合物都具有可检测的亲和力，或者其中两种化合物具有亚微米亲和力。所有三种化合物对 κ 阿片受体均具有低纳摩尔亲和力，对 μ 和 δ 具有中等选择性（3 至 44 倍）。Nor-BNI 对 α(2C)-肾上腺素受体的亲和力较弱（K(i) = 630 nM）。GNTI 增强去甲肾上腺素在 α(1A)-肾上腺素受体上引起的钙动员（EC₅₀ = 41 nM），但不会激活受体、置换放射性配体或增强 PI 水解。这表明它是一种功能选择性的变构增强剂。GNTI 也是一种较弱的 M₁ 受体拮抗剂（K(B) = 3.7 μM）。JDTic 与去甲肾上腺素转运体结合（K(i) = 54 nM），但抑制转运的作用较弱（IC₅₀ = 1.1 μM）。JDTic 也与阿片样受体 NOP 结合（K(i) = 12 nM），但即使在 30 μM 时也几乎没有拮抗作用。三种化合物均能快速穿过 Caco-2 细胞单层并进行主动外排。
在 43 种非阿片类中枢神经系统靶点中，只有 GNTI 表现出强烈的功能效应（变构增强 α(1A)-肾上腺素受体）。这可能导致 GNTI 出现严重的瞬时作用。Nor-BNI 和 GNTI 的血浆浓度可能足够高，足以影响一些外周非阿片类靶点。尽管如此，在这些瞬时作用消散后，κ 阿片受体拮抗作用仍持续数周或数月。经过适当的预给药间隔，我们的结果因此加强了 Nor-BNI、GNTI 和 JDTic 是高度选择性 κ 阿片受体拮抗剂的证据。
