Selective κ Opioid Antagonists nor-BNI, GNTI and JDTic Have Low Affinities for Non-Opioid Receptors and Transporters

Background: 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. Results: In binding assays, the three antagonists showed no detectable affinity (Ki≥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 α2C-adrenoceptor (Ki = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α1A-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 (KB = 3.7 µM). JDTic bound to the noradrenaline transporter (Ki = 54 nM), but only weakly inhibited transport (IC50 = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (Ki = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers. Conclusions: Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α1A-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

Sigma-2 Receptors as Potential Novel Biomarkers During the Progression of Benign Prostatic Hypertrophy (BPH) into Prostate Cancer

Abstract: BPH could be considered the most common benign tumor for men between 60 and 75 years of age. PSA is an unsatisfactory biomarker to define BPH progression to cancer. Recently, sigma-2 receptors have been recognized in several prostate cancer cell lines such as PC-3, DU-145 and LNCaP. It is reported that, in some cases, BPH could progress to malignancy and this progression can not easily be monitored by biomarkers such as PSA. In this paper we investigated 10 specimens from TURP, finding overexpression of sigma-2 receptors in two of these specimens (specimen 1 and 2) accompanied by 4 ng/mL PSA values. We hypothesize that the presence of sigma-2 receptors is related to a BPH progressing in prostate cancer. A possible correlation between sigma-2 receptors and PSA values could be useful to identify this pathological progression

Synthesis and characterization of environment-sensitive fluorescent ligands for human 5-HT<SUB>1A</SUB> receptors with 1-arylpiperazine structure

A series of "long-chain" 1-(2-methoxyphenyl)piperazine derivatives containing an environment-sensitive fluorescent moiety (4-amino-1,8-naphthalimide, 4-dimethylaminophthalimide, dansyl) was synthesized. The compounds displayed very high to moderate 5-HT<SUB>1A</SUB> receptor affinity and good fluorescence properties.6-Amino-2-[5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione (4) combined very high 5-HT<SUB>1A</SUB> receptor affinity (K<SUB>i</SUB> = 0.67 nM), high fluorescence emission in CHCl<SUB>3</SUB>, and undetectable fluorescence emission in aqueous solution. It was evaluated for its ability to visualize 5-HT<SUB>1A</SUB> receptors overexpressed in CHO cells by fluorescence microscopy

CARATTERISTICHE SENSORIALI DEL PECORINO DI LATICAUDA A DIVERSI PERIODI DI MATURAZIONE

Al fine di contribuire alla individuazione del periodo ottimale di maturazione e alla definizione di un disciplinare di tipicità del pecorino di Laticauda, sono state valutate le caratteristiche sensoriali del prodotto a 4 periodi di stagionatur

Effect of some P-glycoprotein modulators on Rhodamine-123 absorption in guinea-pig ileum

Several reference compounds such as Cyclosporin A, Tamoxifen, Verapamil, and our compound 1, known as P-gp modulators, have been tested for their P-gp modulating activity in isolated organ bath. Compound 1 showed the best result in organ bath experiment (EC(50)=14.7 microM), Cyclosporin A and Tamoxifen displayed EC(50)=25.2 and 39.4 microM, respectively

In vitro and ex vivo characterization of sigma-1 and sigma-2 receptors: agonists and antagonists in biological assays

Methods for addressing sigma receptor affinity and activity have been explored and although several protocols have been employed, only few procedures resulted reliable. Sigma-1 receptor affinity protocol using guinea-pig brain and (+)-[(3)H]-pentazocine and sigma-2 receptor affinity protocol employing rat liver and [(3)H]-DTG are usually reported by authors as standard procedures. By contrast, the intrinsic activity evaluation of sigma ligands has been performed in several manners: tumor cell lines, isolated organ bath, in vivo animal model. The last is not considered in the present paper because this method studied the physiological role of sigma receptors. The studies carried out in tumor cell lines involved the role of sigma receptors in tumors progression while, although isolated organ bath experiment employed physiological samples, the pharmacokinetic properties of ligands, a strictly requirement for the in vivo assays, did not affect the pharmacodynamic properties of tested compounds. The advances in the above mentioned assays have been reported

Preliminary results of a proteomic study on fiocco from Casertana ham at the end of seasoning.

The work identified the most hydrolysed myofibrillar proteins and polypeptide components of Fiocco, a traditional italian product from pork leg, after 12 months of seasoning