Analgesic transient receptor potential vanilloid-1-active compounds inhibit native and recombinant T-type calcium channels

Background and Purpose: T-type calcium (Cav3) and transient receptor potential vanilloid-1 (TRPV1) channels play central roles in the control of excitability in the peripheral nervous system and are regarded as potential therapeutic pain targets. Modulators that either activate or inhibit TRPV1-mediated currents display analgesic properties in various pain models despite opposing effects on their connate target, TRPV1. We explored the effects of TRPV1-active compounds on Cav3-mediated currents. Experimental Approach: Whole-cell patch clamp recordings were used to examine the effects of TRPV1-active compounds on rat dorsal root ganglion low voltage-activated calcium currents and recombinant Cav3 isoforms in expression systems. Key Results: The classical TRPV1 agonist capsaicin as well as TRPV1 antagonists A-889425, BCTC, and capsazepine directly inhibited Cav3 channels. These compounds altered the voltage-dependence of activation and inactivation of Cav3 channels and delayed their recovery from inactivation, leading to a concomitant decrease in T-type current availability. The TRPV1 antagonist capsazepine potently inhibited Cav3.1 and 3.2 channels (KD \u3c 120 nM), as demonstrated by its slow off rate. In contrast, neither the TRPV1 agonists, Palvanil and resiniferatoxin, nor the TRPV1 antagonist AMG9810 modulated Cav3-mediated currents. Conclusions and Implications: Analgesic TRPV1-active compounds inhibit Cav3 currents in native and heterologous systems. Hence, their analgesic effects may not be exclusively attributed to their actions on TRPV1, which has important implications in the current understanding of nociceptive pathways. Importantly, our results highlight the need for attention in the experimental design used to address the analgesic properties of Cav3 channel inhibitors

Solvatochromic and quantum chemical investigations of newly synthesized succinimides: substituent effect on intramolecular charge transfer

Two series of 1-aryl-3-phenyl- and 1-aryl-3,3-diphenylpyrrolidine-2,5-diones were synthesized and their solvatochromic properties were studied in a set of 15 solvents of different polarity. The effect of specific and non-specific solvent-solute interactions on the position of their absorption bands was evaluated by using the solvent parameter sets of Kamlet and Taft. The interpretation of the effect of different substituent patterns on the solvatochromic properties of the investigated compounds was based on quantum chemical calculations performed by the density functional theory (DFT)/CAM-B3LYP method using the 6-311G(d,p) basis set. The theoretical absorption frequencies show very good agreement with the experimental values. The energy gaps between the HOMO and LUMO orbitals were also analyzed. It is demonstrated that different substituents change the conjugation effect and further determine the pathways of intramolecular charge transfer