Synthesis and Opioid Activity of Tyr¹‐ψ[(Z)CF=CH]‐Gly² and Tyr¹‐ψ[(S)/(R)‐CF₃CH‐NH]‐Gly² Leu‐enkephalin Fluorinated Peptidomimetics

Abstract

We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1–ψ[(Z)CF=CH]–Gly2) and trifluoroethylamine (Tyr1–ψ[(S)/(R)-CF3CH–NH]–Gly2) analogues of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exihibited low nanomolar functional activity (5.0 ± 2 nM and 60 ± 15 nM for δ- and μ–opioid receptors, respectively) with a μ/δ-selectivity ratio that mimicked the natural peptide. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position.

Tyr1-ψ[(Z)CF═CH]-Gly2 Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin

“…In our previous work, Tyr 1 - ψ [( Z )CF=CH]-Gly 2 substitution provided a 5 nM DOR full agonist ( 2 ) with similar selectivity to the endogenous peptide though 60 fold less potent than the parent peptide ( 1 ), though both ( R )- and ( S )-isomers of Tyr 1 -ψ[CF 3 CH 2 –NH]-Gly 2 analogs ( 3–4 ) did not activate the DOR. 31 Despite the decreased activities, the stability, metabolism, and distribution properties of all analogs were not previously assessed.…”

“…Tyr 1 - ψ [( Z )CF=CH]-Gly 2 -Leu-enkephalin ( 2 ), Tyr 1 - ψ [( R )-CF 3 CH 2 –NH]-Gly 2 -Leu-enkephalin ( 3 ), and Tyr 1 - ψ [( S )-CF 3 CH 2 –NH]-Gly 2 -Leu-enkephalin ( 4 ) were synthesized according to previously reported procedures. 31 Confirmation of the identity and purity of 2–4 was accomplished by a combination of 1 H, 19 F, and 13 C NMR, HRMS, and UPLC.…”

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

“…The defluorinative reduction could also be performed using samarium iodide. Altman and co-workers proposed the synthesis of Boc-Tyr-ψ[( Z )-CF=CH]-Gly using a diastereoselective Reformatsky–Honda condensation, a ( E )-selective HWE olefination and a SmI 2 reduction as key steps ( Scheme 12 ) [ 41 ]. First, Reformatsky–Honda reaction of TIPS-protected phenylacetaldehyde 57 with the chiral auxiliary ( L )-phenylglycine derivative 58 afforded 59 .…”

“…Altman and co-workers also studied a fluorinated mutant of the Leu-enkephaline [ 41 ]. The isostere Boc-Tyr-ψ[( Z )-CF=CH]-Gly (see Scheme 12 ) was coupled to a tripeptide to afford Boc-Tyr-ψ[( Z )-CF=CH]-Gly-Gly-Phe-Leu.…”

N‐Arylation of Fluoroalkylamine and Trifluoroacetamide through Cu–Catalysis

“…For instance, the introduction of fluorine into β‐position of N‐arylamine and arylamide can protect them against oxidation and enhance bioactivity . β‐CF 3 amine and amide group(CF 3 CH 2 NH 2 , CF 3 CONH 2 ) have been probe more valuable than the parent aniline, thus, the synthesis of β‐CF 3 aryl‐amine and amide have driven much attention over the past few years …”