RT Journal Article
SR Electronic
T1 Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.22.453441
DO 10.1101/2021.07.22.453441
A1 Václav Havel
A1 Andrew C. Kruegel
A1 Benjamin Bechand
A1 Scot McIntosh
A1 Leia Stallings
A1 Alana Hodges
A1 Madalee G. Wulf
A1 Melissa Nelson
A1 Amanda Hunkele
A1 Mike Ansonoff
A1 John E. Pintar
A1 Christopher Hwu
A1 Najah Abi-Gerges
A1 Saheem A. Zaidi
A1 Vsevolod Katritch
A1 Mu Yang
A1 Jonathan A. Javitch
A1 Susruta Majumdar
A1 Scott E. Hemby
A1 Dalibor Sames
YR 2021
UL http://biorxiv.org/content/early/2021/07/23/2021.07.22.453441.abstract
AB Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities.1,2 Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction states, highlighting an urgent need for radically different therapeutic approaches.3,4 Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt maladaptive habits including opioid use in drug-dependent humans.5 However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias.6 We introduce a new class of iboga alkaloids - “oxa-iboga” - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in addiction models and no cardiac pro-arrhythmic potential, compared to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine intake after a single dose in rat models of addiction and persistent reduction of morphine intake after a short treatment regimen. Oxa-noribogaine maintains and enhances the ability of iboga compounds to effect lasting alteration of addiction-like states while addressing iboga’s cardiac liability. As such, oxa-iboga compounds represent candidates for a new kind of anti-addiction pharmacotherapeutics.Competing Interest StatementV.H., A.C.K, B.B., M.G.W, J.A.J., S.E.H and D.S. are named inventors on a patent(s) related to oxa-iboga compounds. A.C.K and D.S. are co-founders of Gilgamesh Pharmaceuticals. All other authors declare no competing interests.