1. Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies
- Author
-
Anna K. Sundgren-Andersson, Erik Sjögren, O. Stålberg, and Magnus M. Halldin
- Subjects
Male ,0301 basic medicine ,Analgesic ,Central nervous system ,TRPV1 ,Pain ,TRPV Cation Channels ,CHO Cells ,Pharmacology ,03 medical and health sciences ,Transient receptor potential channel ,chemistry.chemical_compound ,Cricetulus ,0302 clinical medicine ,MicroDose ,Cricetinae ,Ganglia, Spinal ,Animals ,Medicine ,Pharmaceutical sciences ,Analgesics ,Behavior, Animal ,Dose-Response Relationship, Drug ,biology ,business.industry ,musculoskeletal, neural, and ocular physiology ,biology.organism_classification ,Rats ,030104 developmental biology ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,nervous system ,chemistry ,Capsaicin ,lipids (amino acids, peptides, and proteins) ,business ,030217 neurology & neurosurgery - Abstract
The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies.The inhibitory effectiveness was evaluated by means of in vitro assays, TRPV1 expressing Chinese hamster ovary cells (CHO-K1) and rat dorsal root ganglion cultures in fluorescent imaging plate reader and whole cell patch clamp systems, as well as in vivo by capsaicin-evoked pain-related behavioural response studies in rat. Secondary pharmacology, pharmacokinetics and preclinical safety were also assessed.In vitro, all three compounds were effective at inhibiting capsaicin-activated TRPV1. The concentration producing 50% inhibition (ICThe investigated model compounds displayed ideal compound characteristics as pharmacological and translational tools to address efficacy on the human native TRPV1 target in human skin in situ.This work details the pharmaceutical work-up of three TRPV1-active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost-effective preclinical development path may impact research beyond the pain management area, as it allows human target engagement information gathering early in drug development.
- Published
- 2018