New antagonists for the Kappa Opioid receptor

Abstract

There has been much evidence in recent years to suggest that the kappa
opioid receptor plays a significant role in mediating a number of behavioural
disorders including drug abuse and depression. Previous in vitro evaluation
within the group of secondary and tertiary amines derived from 2-amino-1,1-
dimethyl-1,2,3,4-tetrahydronaphthalen-7-ol has suggested that all behave as pure
opioid antagonists. These findings prompted further synthetic and
pharmacological investigations of this scaffold, with the eventual aim of
developing a short-acting selective kappa opioid antagonist to further probe the
receptor.
A synthetic route to the individual enantiomers of 2-amino-1,1-dimethyl1,2,3,4-tetrahydronaphthalen-7-ol was developed utilising the formation of chiral
imines and the subsequent reduction. The individual stereoisomers of the lead
compounds were synthesised. The absolute configuration was confirmed by
crystallography and HPLC confirmed the high enantiomeric excesses achieved by
this synthesis. Pharmacological evaluation has shown the (S)-enantiomers to have
higher affinity and more potent antagonist activity at opioid receptors.
The encouraging results obtained for aminotetralins with a OCH3 group in
the 3-position of the aminotetralin prompted further investigation. The individual
enantiomers of the N-cinnamyl analogue were separated by chiral HPLC. A series
of N-substituted ligands utilising the aminotetralin scaffold bearing a 3-SCH3
substituent were synthesised. Pharmacological results indicate a considerable gain
in opioid receptor binding whilst retaining pure antagonist activity.
Based on a literature review of SAR for opioid binding a new scaffold was
identified: 2-(aminomethyl)-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-7-ol. A
synthetic route was devised and preliminary compounds submitted for evaluation.
An investigation to determine whether the aminotetralin scaffold would allow
access to short-acting KOP antagonists was also carried out. Compounds
containing a metabolically labile ester functionality were targeted and a
metabolism study in human blood was developed.

Date of Award	1 Jun 2009
Original language	English
Awarding Institution	University of Bath
Supervisor	Stephen Husbands (Supervisor)