Optimization of Betulinic Acid analogs for T-type calcium channel inhibition for non-addictive relief of chronic pain

ABSTRACT Chemotherapy induced peripheral neuropathyCIPNis a commonprevalenceand potentially doselimiting side effect of many cancer chemotherapy drug treatment regimensClinicallyCIPN presents with pain that is burningshooting or electric shock likeThe increase in prevalence of cancer coupled with an increase in the cancer survival rates due to chemotherapy regimens is transforming cancer pain into a largeunmet medical problemNeurotoxic chemotherapeutic agentse gantimicrotubule agents like paclitaxelmay cause structural damage to peripheral nervesresulting in aberrant somatosensory processing in the peripheral and or central nervous systemDorsal root gangliaDRGsensory neurons as well as neuronal cells in the spinal cord are the preferential sites in which chemotherapy induced neurotoxicity occursPathogenesis is complex but includes alterations in ion channelsPaclitaxelTaxolincreases T typeCavvoltage gated Cacurrents in rat dorsal root ganglionDRGneuronsthese neurons are responsible for conveying noxious sensory stimulisuggesting these channels are important mediators of specific sensory abnormalities associated with CIPNGiven the roles of these channels in regulating afferent fiber excitability and synaptic function in the spinal dorsal horn and their dynamic regulation during pain statesblocking or depleting Cavchannels in these tissues should mediate analgesic effectsIn the pastyearsconsiderable effort has been applied towards identifying novel classes of T type calcium channel blockersThis proposal aims to develop potentorally availableand selective Cavchannel antagonistsbuilding on the structure of a natural productbetulinic acidBAidentified by the laboratory of DrLeslie GunatilakaDirectorNatural Products CenterUniversity of ArizonaUAand characterized by the PI DrRajesh KhannaUAto be Cavselective and antinociceptive in CIPNFor this workwe have partnered with RegulonixLLC for characterizing select Cavtargeted compounds and their analogs in in vitro and in vivo efficacy assays as well as early ADME and PK optimizationThe work proposed here is the first step in developing non opioid pain treatments for CIPN that also curb opioid misuse and addictionWe anticipate success against paclitaxel induced chronic pain to translate into other chronic pain types as wellbut CIPN provides focus for early stage proof of conceptRegulonix s specific aims areDesign and synthesisDrLGunatilakaof BA analogues and elucidation of Cavspecificity and biophysical properties of select BA analogs to gain mechanistic and safety information and to document the unique pathway for function in neuronsProfile BA analogues for their in vitro cellular cytotoxicityearly ADME and pharmacokinetic propertiesand screening for off target effects on GPCRsion channels and alternative known pain targetsincluding opioid receptorsandCharacterize the best two BA analogsfrom Aimfor preclinical studies using a neuropathic pain modelpaclitaxelto provide information about oral efficacysafetyand opioidsparingUpon completionwe expect to have a validated BA analog and several worthy backup compounds NARRATIVE Medicinal plants represent a significant reservoir of unexplored substances for early stage drug discoveryHereRegulonix LLC proposes to develop novel small molecules to target low voltage activated T type calciumCavchannela key protein in pathogenesis of neuropathic pain including chemotherapy induced peripheral neuropathyCIPNWe will design orally available T type channel antagonistsanalogs of the extract betulinic acidBAwhich we recently discovered from a desert lavender plantFirstchannel specificity and biophysical properties of the best Cavantagonists will be elucidated to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells including human neuronsNextBA analogs will be tested in a neurotoxicity modelrotarodand cellular pharmacological assays that provide information about efficacy and functionWhether BA analogs are opioid sparing will also be testedFinallydrug properties of an optimized Cavantagonist and its in vivo effectiveness will be determined in the paclitaxel model of CIPN