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Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABA A receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex., Competing Interests: Declaration of competing interest The authors declare no competing financial interests or personal relationships that could have influenced the current work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS). Ibogalogs decreased mechanical hyperalgesia and allodynia induced by CCI in a dose- and timeframe-dependent manner, where IBG showed the longest anti-hyperalgesic activity at a comparatively lower dose, whereas DM506 displayed the quickest response. These compounds also decreased hypersensitivity induced by colitis, where DM506 showed the longest activity. To understand the mechanisms involved in these effects, two approaches were utilized: ibogalogs were challenged with the 5-HT 2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT 2A, 5-HT 6 , and 5-HT 7 receptor subtypes. The behavioral results clearly demonstrated that ketanserin abolishes the pain-relieving activity of ibogalogs without inducing any effect per se, supporting the concept that 5-HT 2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT 2A and 5-HT 6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT 7 receptor. Considering previous studies showing that 5-HT 6 receptor inhibition, but not activation, and 5-HT 7 receptor activation, but not inhibition, relieved chronic pain, we can discard these two receptor subtypes as participating in the pain-relieving activity of ibogalogs. The potential involvement of 5-HT 2B/2 C receptor subtypes was also ruled out. In conclusion, the anti-hypersensitivity activity of ibogalogs in mice is mediated by a mechanism involving 5-HT 2A receptor activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13 , 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.

The anxiolytic and sedative-like effects of 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (DM506), a non-hallucinogenic compound derived from ibogamine, were studied in mice. The behavioral effects were examined using Elevated O-maze and novelty suppressed feeding (NSFT) tests, open field test, and loss of righting reflex (LORR) test. The results showed that 15 mg/kg DM506 induced acute and long-lasting anxiolytic-like activity in naive and stressed/anxious mice, respectively. Repeated administration of 5 mg/kg DM506 did not cause cumulative anxiolytic activity or any side effects. Higher doses of DM506 (40 mg/kg) induced sedative-like activity, which was inhibited by a selective 5-HT 2A receptor antagonist, volinanserin. Electroencephalography results showed that 15 mg/kg DM506 fumarate increased the transition from a highly alert state (fast γ wavelength) to a more synchronized deep-sleeping activity (δ wavelength), which is reflected in the sedative/anxiolytic activity in mice but without the head-twitch response observed in hallucinogens. The functional, radioligand binding, and molecular docking results showed that DM506 binds to the agonist sites of human 5-HT 2A (Ki = 24 nM) and 5-HT 2B (Ki = 16 nM) receptors and activates them with a potency (EC 50 ) of 9 nM and 3 nM, respectively. DM506 was relatively less potent and behaved as a partial agonist (efficacy <80%) for both receptor subtypes compared to the full agonist DOI (2,5-dimethoxy-4-iodoamphetamine). Our study showed for the first time that the non-hallucinogenic compound DM506 induces anxiolytic- and sedative-like activities in naïve and stressed/anxious mice in a dose-, time-, and volinanserin-sensitive manner, likely through mechanisms involving 5-HT 2A receptor activation., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed.

New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized as tariquidar and elacridar derivatives and studied as multidrug resistance (MDR) reversers. Their behaviour on the three ABC transporters P-gp, MRP1 and BCRP was investigated. All compounds inhibited the P-gp transport activity in MDCK-MDR1 cells overexpressing P-gp, showing EC 50 values even in the low nanomolar range (compounds 15, 22). Oxadiazole derivatives were able to increase the antiproliferative effect of doxorubicin in MDCK-MDR1 and in HT29/DX cells confirming their nature of P-gp modulators, with derivative 15 being the most potent in these assays. Compound 15 also displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP. A computational study suggested a common interaction pattern on P-gp for most of the potent compounds. The bioisosteric substitution of the amide group of lead compounds allowed identifying a new set of potent oxadiazole derivatives that modulate MDR through inhibition of the P-gp efflux activity. If compared to previous amide derivatives, the introduction of the heterocycle rings greatly enhances the activity on P-gp, introduces in two compounds a moderate inhibitory activity on MRP1 and maintains in some cases the effect on BCRP, leading to the unveiling of dual inhibitor 15., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)