Understanding methiopropamine, a new psychoactive substance: an in-depth review on its chemistry, pharmacology and implications to human health.

Methiopropamine or 1-(thiophen-2-yl)-2-methylaminopropane (MPA) is a thiophene ring-based structural analogue of methamphetamine, first synthesized in 1942 but become popular when it started to be available for purchase on websites selling 'legal highs' since 2010. While it is legally controlled in many countries, it remains readily accessible and frequently encountered in recreational settings. The growing prevalence of MPA use results in new therapeutic challenges. Relatively few studies have focused on its pharmacodynamics and pharmacokinetics, making it important to better understand its potential risks and harmful effects in humans in terms of its toxicity. This review provides a comprehensive profiling of MPA toxicological properties, including its chemical properties, analytical methods, prevalence, patterns of use, and legal status. Additionally, it discusses the drug's effects on the central nervous system, its potential for addiction, and its adverse physical and mental health effects. Improving the understanding of safety aspects of MPA and how it imposes health threats for public health will guide the development of therapeutic approach of its intoxication and guide the authorities in deciding its legal status.

Potential Roles of 5-HT3 Receptor Antagonists in Reducing Chemotherapy-induced Peripheral Neuropathy (CIPN).

5-HT3 receptor antagonists corresponding to ondansetron, granisetron, tropisetron, and palonosetron are clinically accustomed to treating nausea and emesis in chemotherapy patients. However, current and previous studies reveal novel potentials of those ligands in other diseases involving the nervous system, such as addiction, pruritus, and neurological disorders, such as anxiety, psychosis, nociception, and cognitive function. This review gathers existing studies to support the role of 5-HT3 receptors in CIPN modulation. It has been reported that chemotherapy drugs increase the 5-HT content that binds with the 5-HT3 receptor, which later induces pain. As also shown in pre-clinical and clinical studies that various neuropathic pains could be blocked by the 5-HT3 receptor antagonists, we proposed that 5-HT3 receptor antagonists via 5- HT3 receptors may also inhibit neuropathic pain induced by chemotherapy. Our review suggests that future studies focus more on the 5-HT3 receptor antagonists and their modulation in CIPN to reduce the gap in the current pharmacotherapy for cancer-related pain.

Potential roles of 5-HT3 receptor (5-HT3R) antagonists in modulating the effects of nicotine.

5-HT3R antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current study and research revealed novel potentials of these ligands in other diseases like inflammation, Alzheimer's, and drug abuse. Towards utilising these drugs as anti-smoking agents to treat nicotine dependence problem, there are conflicting reports regarding the potential of these ligands in modulating the effects of nicotine in both human and animal behavioural studies. This is complicated by the heterogeneity of 5-HT3R itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HT3R antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HT3R antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HT3R antagonists mediate the effects of nicotine could be attributed by both direct at 5-HT3R and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HT3R antagonist could be through α7 nAChR, 5-HT1B receptor (5-HT1BR), 5-HT1C receptor (5-HT1CR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κß. Our review suggested that future studies should focus on newer 5-HT3R antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.

The C and E subunits of the serotonin 5-HT3 receptor subtly modulate electrical properties of the receptor.

Serotonin type 3 (5-hydroxytrptamine-3, 5-HT3) receptors are ligand-gated cation channels present in both central and peripheral nervous systems. In humans there are five different subunits (A, B, C, D and E) of 5-HT3 receptors which can form homomeric or heteromeric receptors that may account for discrepancies in patient responses to treatments. The present study commences characterisation of the profiles of human 5-HT3 receptors containing C and/or E subunits. Recombinant 5-HT3 receptors were expressed transiently in HEK293T cells and expression was checked via immunocytochemistry staining against each epitope-tagged subunits. Functional characterisation of different combinations of 5-HT3 receptor complexes was studied via patch clamp whole cell recordings. In this study, increased current was seen in cells containing A and C subunits but only subtle changes were seen in the electrical properties of cells expressing A, AE, or ACE subunits in response to the ligand, 5-HT. Both di- and tri-heteromeric 5-HT3 receptors were significantly inhibited by the antagonists, ondansetron and palonosetron. Notably, palonosetron exerted stronger and more rapid inhibition on the 5-HT3 receptor ACE tri-heteromer compared to homomeric and di-heteromeric counterparts. This study demonstrated that the C and E subunits when assembled as simple or complex heteromeric 5-HT3 receptors may alter efficacies of 5-HT and clinically used antagonists such as ondansetron and palonosetron, and this in turn may have implications for patient responses to therapies.