Enkephalin mimetics

F ure 3.28. Peptidomimetics that have been designed based on iterative introduction of constraints into parent peptide and hypotheses concerning receptor-bound conformation. Enkephalin mimetic (388), RGD platelet GPIIb/IIIa receptor antagonists (384,385), thyrohberin [TRH (387)], and somatostatin (383,389).For an overview of recent approaches to peptidomimetic design, see the review by Bursavich and Rich (382). 

Fig. 29.14 Enkephalin mimetics with a p-turn at Gly2 and Gly3.

Frejd and coworkers then used lactam 45 as a structural H-Phe-Phe-OH mimic in peptides (116). The resulting conjugate 48 was expected to function as a structural mimic of substance P (Scheme 5.25). However, CD spectroscopic studies indicated that the constraints imposed by the l,l -ferrocenophane prohibited the peptide to adopt the characteristic a-hehcal secondary structure found for native SP in a biomimetic SDS (Sodium n-Dodecyl Sulfate) micellar environment. In another interesting paper, Frejd and coworkers prepared a [Leu ]-Enkephalin mimetic in which the H-Tyr-Gly-Gly-Phe-subunit has been replaced by a Gly-Gly-looped l,l -ferrocenyl-bis-alanine residue (49, Scheme 5.25) [117]. The ferrocene Cp rings of this constrained compound constitute a substitute for the aromatic phenol (Tyr) and phenyl (Phe) rings. NMR-spectroscopic studies revealed this... 

Compounds 32 and 33 (Scheme 13), reported in the 1980s,1t79,80 were designed as mimetics of the pentapeptide Met-enkephalin. Both compounds had very poor biological activity, which could be attributable to a number of features. 

Similarly, a turn mimetic analogue of Leu-enkephalin (Scheme 27) was prepared.1"11 The compound exhibited significant in vivo analgesia despite relatively low affinity in a binding assay. 

Huffman et alJ161 have also incorporated a /ram-alkene y-turn mimetic into a series of enkephalin analogues 14 (Scheme 9) with complete loss of biological activity and into an HIV-1 protease inhibitor replacing the -Asn-Tyr-Pro- sequence in 15 corresponding to the P2-Pi-P( positions of the peptide substrate giving 16[39-401 (Scheme 10). 

Scheme 9 Incorporation of a Pww-Alkene y-Turn Mimetics in a Series of Enkephalin Analogues1161...

The same group has also reported the synthesis of the nonpeptide enkephalin (3-tum mimetic 216 [162]. The key step of the approach, Scheme 64, involves the simultaneous intramolecular cyclization/(3-lactam ring cleavage in derivative 215 leading to compound 216. 

The opioid alkaloids are classic examples of non-peptide ligands that have later been discovered to be mimetics of endogenous peptides. For example, morphine 5 (Figure 1.4.3) imitates the effect of flexible peptides, for example Met-enkephalin 4, at the common recognition site of the receptor for both compounds... 

Blomberg, D., Kreye, P., Fowler, C., Brickmann, K., and Kihlberg, J. (2006) Synthesis and biological evaluation of leucine enkephalin turn mimetics. Org Biomol Chem 4, 416-423. 

Fig. 29.16 Diversity components for enkephalin and endomorphin p-turn mimetics.

Table 29.2 Nonselective opioid receptor binding assay of enkephalin and endomorphin ji-turn mimetics...

Gardner, B., Nakanishi, H. and Kahn, M. (1993) Conformationally constrained nonpeptide P-tum mimetics of enkephalin. Tetrahedron 49 3433-3448. 

Kahn and co-workers at the University of Illinois at Chicago noted that a number of turn conformations had been proposed for the enkephalins based on computational models. X-ray crystallography, and spectroscopic studies. To test the hypothesis that a 2 — 5 p-turn was a biologically relevant conformation, these authors investigated the mimetic 79. They energy-... 

B. Gardner, H. Nakanishi, and M. Kahn, Tetrahedron, 49, 3433 (1993). Conformationally Constrained Nonpeptide p-Turn Mimetics of Enkephalin. 

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