Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist

Abstract

A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3′,5′-(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3)2-Bn] and 23 [Ac-Tic-NMe-3′,5′-(CF3)2-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R. The most active NK1 antagonist of the series, 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3)2-Bn], was then used in the design of a novel, potent chimeric opioid agonist-NK1 receptor antagonist, 35 [Dmt-D-Arg-Aba-Gly-NMe-3′,5′-(CF3)2-Bn], which combines the N-terminus of the established Dmt1-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH2) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, i.e. Dmt-D-Arg-Aba-Gly-NH2 36, also proved to be an extremely potent and balanced μ- and δ opioid receptor agonist with subnanomolar binding and in vitro functional activity.

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

“…The cis / trans ratio of the amide bond between residue 4 and the C-terminal benzylamine moiety in lead compound 4 was investigated by NMR analysis and was estimated to be 35:65. Results obtained by molecular modeling also confirmed one of the three lowest energy conformations in the NK1R pharmacophore to adopt the cis amide geometry, 24 and hence this orientation could be important for NK1R activity. In an attempt to increase the cis / trans ratio, a N - i Bu group was used instead of the N -Me motif.…”

“…The in vitro biological evaluation of 4 showed that combination of the two components gratifyingly resulted in good binding affinity for both opioid and NK1R receptors. 24 Furthermore, the compound showed antinociceptive activity after intravenous administration in vivo , and hence the hybrid structure proved, similarly to the parent opioid sequence Dmt-D-Arg-Aba-Gly-NH 2 7 , 29 capable of crossing the blood-brain barrier (BBB). Unfortunately, hybrid 4 still produced analgesic tolerance in naive animals.…”

“…24 The opioid subunit in 4 is derived from the μ opioid receptor lead peptide Dmt-D-Arg-Phe-Lys-NH 2 ([Dmt 1 ]DALDA) 5 , 25 and contains a constrained Aba (4- a mino-2- b enz a zepinone) 26-28 moiety in position 3. As this conformationally constrained amino acid was also the core structure of a newly developed NK1 antagonist, 24 Ac- Aba -Gly- N Me-3’,5’-(CF 3 ) 2 -Bn ( 6 ) (corresponding to the blue part in structure 4 , Figure 1), the combination of both ligands led to the hybrid structure Dmt-D-Arg- Aba -Gly- N Me-3’,5’-(CF 3 ) 2 -Bn 4 , a DML with overlapping pharmacophores. The in vitro biological evaluation of 4 showed that combination of the two components gratifyingly resulted in good binding affinity for both opioid and NK1R receptors.…”

Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice

“…1,2 Both compounds have a N -methylated amide group in the C-terminal NK1 pharmacophore, which is essential for affinity and antagonism at the NK1 receptor. 1 Whereas secondary amide groups adopt exclusively a trans conformation, tertiary amides exist as a mixture of cis and trans isomers with a reduced activation energy for rotation. 17 Since a large percentage of cis isomers (18–22%) was found in an earlier study of NK1-ligands, this configuration might be important for activity.…”

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

“…19,20,26 Moreover, the in vivo studies showed activity in acute pain 26 as well as in neuropathic pain models. 20 The potent analgesic responses after intravenous (i.v.)…”