Evaluation of constrained amino acids in the design of neurokinin 1 receptor- and bifunctional opioid - neurokinin 1 receptor ligands

Background and Aim: Polypharmacology is generally
possible in three ways: 1) drug cocktails, 2) multicomponent
drugs and 3) multiple ligands. The first two
methods show disadvantages like poor patient compliance
and drug-drug interactions. Multiple ligands however,
consisting of a single chemical entity that modulates
multiple targets simultaneously, potentially overcome
these drawbacks [Morphy et al., 2005; 2007].
Methods: Earlier research by Lipkowski and Hruby
demonstrated that bifunctional peptides possessing
both NK1R antagonist properties and opioid agonist
potency show advantages over current analgesic
drugs, such as a potent analgesic effect in both acute
and neuropathic pain states, suppression of the development
of tolerance and the presentation of antiallodynic
and antihyperalgesic effects [Bonney et al.,
2004; Hruby et al., 2009; Yamamoto et al., 2010].
Results and Conclusions: Different types of constrained
aromatic amino acids were derivatized to prepare
new neurokinin 1 receptor (NK1R) antagonists.
Subsequent identification of the most potent antagonist
allowed the preparation a chimeric structure possessing
the desired dual opioid-NK1 activity (NK1 Ki
= 0.5 nM, pA2 = 7.8; MOR Ki = 0.4 nM) Our latest
efforts in the construction of this type of ligands will
be presented.