Targeting the hTRPV6 with capsaicinoid inhibitors

Capsaicin is a substance produced by Capsicum peppers with extensive biological activity reported in the literature. Among these studies, it was suggested that the anti-tumor activity is related to modulation of the Transient Potential Receptor Vanilloid (TRPV) channels. Capsaicin is known to bind with very high affinity to TRPV1 (IC50 ≈ 7 nM), triggering the burning sensation followed by analgesia. However, recent studies have suggested that the pro-apoptotic effects of capsaicin are TRPV6-mediated. Herein we report the development of a novel inhibitor of the TRPV6 using two different strategies for compounds design. We generated a series of direct and chimeric capsaicinoids based on the literature compounds, capsaicin, and cis-22a. These analogs were probed against HEK-hTRPV6 and the hits were further optimized. Based on the previous SAR and chemical optimization, we found 56h, named MRC-130, a derivative that remarkably inhibited TRPV6 in the nanomolar range (IC50 = 83 ± 4 nM), possess high selectivity and stability in vitro, and lesser hERG inhibition compared to the reference compound, cis-22a. It is expected that these new molecules would contribute significantly to the study on the TRPV6 function and its role in tumor pathophysiology

Capsaicina é uma substância produzida por pimentas do gênero Capsicum com extensa atividade biológica relatada na literatura. Entre esses estudos, sugeriu-se que a atividade antitumoral esteja relacionada à modulação dos canais TRPV (do inglês, Transient Potential Receptor Vanilloid). Sabe-se que a capsaicina se liga com altíssima afinidade ao TRPV1 (IC50 ≈ 7 nM), desencadeando a sensação de queimação seguida de analgesia. No entanto, estudos recentes sugeriram que os efeitos pró-apoptóticos da capsaicina são mediados pelo TRPV6. Visando o exposto, este trabalho relata o desenvolvimento de um novo inibidor do TRPV6 usando duas estratégias diferentes para o planejamento dos compostos. Geramos séries de capsaicinoides diretos e quiméricos com base nos compostos da literatura, capsaicina e cis-22a. Esses análogos foram analisados contra HEK-hTRPV6 e os análogos mais promissores foram otimizados. Com base na REA e em otimizações químicas anteriores, encontramos 56h, chamado MRC-130, um derivado que inibiu notavelmente o TRPV6 na faixa nanomolar (IC50 = 83 ± 4 nM), possui alta seletividade e estabilidade in vitro e menor inibição de hERG em comparação com o composto de referência, cis-22a. Espera-se que essas novas moléculas contribuam significativamente para o estudo da função do TRPV6 e seu papel na fisiopatologia tumoral

Capsiate treatment in liver surgeries may compromise its recovery

Abstract Purpose: To investigate the effects of capsiate treatment on hepatic hyperplasia in partially hepatectomized rats. Methods: The animals were divided into a Capsiate group (CPH), a Capsiate Post-Partial Hepatectomy group (CPPH) and a Partial Hepatectomy Control group (PH). CPH and CPPH animals received 60 mg/kg/day Capsiate for 30 days. Next, the rats underwent partial hepatectomy. CPPH animals continued to receive treatment for 48 h after partial hepatectomy. Liver tissue and intracardiac blood samples were obtained 24 or 48 h after PH. Results: Capsiate treatment interfered with hepatic parameters, reducing the number of mitoses and apoptosis and increasing blood ALT and alkaline phosphatase concentrations. Conclusion: Capsiate treatment preceding hepatic surgery may compromise the initial period of postoperative recovery.

Interaction between cannabinoid compounds and capsazepine in protection against acute pentylenetetrazole-induced seizure in mice

The pharmacological interaction between cannabinoidergic system and vanilloid type 1 [TRPV1] channels has been investigated in various conditions such as pain and anxiety. In some brain structure including hippocampus, CB1 and TRPV1 receptors coexist and their activation produces opposite effect on excitability of neurons. In this study, we tested the hypothesis that TRPV1 channel is involved in the modulation of cannabinoid effects on pentylenetetrazole [PTZ]-induced seizure threshold. In single therapy, male mice [n = 10 per group] received either TRPV1 receptor antagonist capsazepine, CB1 receptor agonist ACEA or anandamide reuptake inhibitor VDM11. In combination therapy, mice were treated with either capsazepine-ACEA or capsazepine-VDM11 combination prior to seizure test. Thirty min later, mice were submitted to infusion of PTZ [1%, 0.25 mL/min] into tail vein and the dose of PTZ to induce clonic convulsion was considered as seizure threshold. Administration of capsazepine and ACEA per se produced protective effects against PTZ-induced seizure, while administration of VDM11 per se did not produce such a protection effect. The anticonvulsant actions of both capsazepine and ACEA were attenuated after co-administration of these compounds. Moreover, the anticonvulsant action of capsazepine was attenuated after co-administration with VDM11. The results suggest an interaction between cannabinoidergic system and TRPV1 receptors in protection against acute PTZ-induced seizure in mice