Synthesis and biological activity profile of novel triazole/quinoline hybrids.

Based on the significant and diverse pharmacophore features of triazole ring and considering the potent antimicrobial properties of quinoline scaffold, a novel series of 1,2,3-triazole-based polyaromatic compounds containing chloroquinoline moiety were synthesized through a well-established synthetic methodology, named click chemistry. The structure of the synthetic compounds was characterized by various spectroscopic methods. The final products of triazole/quinoline hybrids and ((prop-2-yn-1-yloxy)methyl)benzene intermediates were screened for their antibacterial (Staphylococcus aureus, Escherichia coli, Shigella flexneri, and Salmonella enterica), antifungal (Candida albicans, Saccharomyces cerevisiae, and Aspergillus fumigatus), and cytotoxic activities. The best antifungal compounds exhibited minimum inhibitory concentration (MIC), in the range of 0.35-0.63 µM, against S. cerevisiae without any cytotoxic effect. These compounds can be selected as the potential candidates for treating invasive fungal infections caused by S. cerevisiae, after further investigation. Preliminary in silico ADME studies also predicted the favorable pharmacokinetic attributes of most compounds.

Blockade of orexin receptors in the hippocampal dentate gyrus reduced the extinction latency of morphine-induced place preference in male rats.

Relapse to drugs such as opioids is a major challenge in addiction therapy. It has been known that the orexinergic system has a significant role in mediating reward processing and addiction, as shown by the conditioned place preference (CPP). The dentate gyrus (DG) of the hippocampus receives orexinergic projections from the lateral hypothalamus that has been approved as a critical area arbitrating the maintenance of drug-seeking behavior following the extinction. The present study aimed to investigate the effects of intra-DG administration of the orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R) antagonists on the extinction of morphine-induced CPP in male rats. Animals received different doses of SB334867 (as OX1R antagonist) or TCS OX2 29 (as OX2R antagonist) (0.5, 2.5, and 12.5 nM/0.5 µl DMSO 12 %) bilaterally into the DG during the extinction phase, after CPP had been induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. The conditioning scores were recorded during the test. The results demonstrated that intra-DG administration of the highest dose of OX1R antagonist (12.5 nM/0.5 µl DMSO 12 %) shortened the extinction latency of morphine-CPP compared to the DMSO group, while the OX2R antagonist did not significantly alter the latency. Findings imply that the blockade of OX1R, but not OX2R, within the DG facilitates the extinction of morphine-induced reward. In conclusion, the OX1R antagonist might be kept in mind as a convenient therapeutic factor in repressing drug-seeking behaviors in an optimum amount of treatment considering the low dose-treatments applied.

Cannabidiol modulates the METH-induced conditioned place preference through D2-like dopamine receptors in the hippocampal CA1 region.

The main problem with addiction is a relapse with a high rate in methamphetamine (METH) abusers. Using addictive drugs repetitively will cause the reward. METH reward is due to an increase in dopamine levels, and the endocannabinoid system (ECS) has a modulatory role in reward through CB1 receptors. On the other hand, the hippocampus plays an important role in learning and memory, so it is involved in the neuroplasticity caused by METH abuse. Cannabidiol (CBD) has been shown to reduce the effects of METH through different mechanisms such as increasing the ECS activity, regulating emotional memory in the ventral hippocampus through D2-like dopamine receptors, and decreasing the mesolimbic dopaminergic activity. The present study tried to find out the role of hippocampal CA1 D2-like dopamine receptors (D2R) in the effects of cannabidiol on the acquisition and expression of METH-induced conditioned place preference (METH-CPP) in rats by using microinjection of sulpiride as a D2R antagonist. For this purpose, different groups of animals received different doses of sulpiride (0.25, 1, and 4 µg/0.5 µL DMSO; CA1), once prior to the injection of CBD (10 µg/5 µL for acquisition and 50 µg/5 µL for expression; ICV) and once in the absence of CBD. Control groups were also considered. In brief, findings showed that cannabidiol decreases METH-induced CPP. Intra-CA1 administration of sulpiride reversed the decreasing effects of cannabidiol on METH-induced CPP in both acquisition and expression phases but more prominent in the expression phase. The results showed that sulpiride did not affect the METH-induced CPP in the absence of cannabidiol. In conclusion, this study demonstrated that cannabidiol decreased METH-induced CPP in part through interaction with hippocampal CA1 D2-dopamine receptors.

Role of orexinergic receptors in the dentate gyrus of the hippocampus in the acquisition and expression of morphine-induced conditioned place preference in rats.

Orexinergic projections derived from the lateral hypothalamus (LH) play a crucial role in the acquisition and expression of morphine-conditioned place preference (CPP). It has been demonstrated in previous that orexinergic receptors are expressed in the dentate gyrus (DG) region of the hippocampus, which receives projections of LH orexinergic neurons. This study examined the effects of intra-DG orexin-1 (OX1) and orexin-2 (OX2) receptor antagonists on the acquisition and expression of CPP induced by morphine. Two separate cannulas were inserted bilaterally into the DG, and a CPP paradigm was performed. The CPP scores and locomotor activities were recorded using Ethovision software. The results showed that intra-DG microinjection of SB334867 as a selective OX1R antagonist (0.5, 2.5, 12.5 nM/0.5 µl DMSO) or TCSOX229 as a selective OX2R antagonist (0.5, 2.5, 12.5 nM/0.5 µl DMSO) before a morphine subcutaneous injection (5 mg/kg) during a three-day conditioning phase dose-dependently represses the acquisition of morphine-induced CPP in rats. Furthermore, these antagonists reduced the CPP scores in the expression phase. Consequently, it was established that orexinergic receptors in the DG are involved in the acquisition and expression of morphine-induced CPP.