Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Enkephalin Analogues

Abstract

It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended conformations of oligopeptides, and molecular modeling studies now suggest that the corresponding cis-cyclopropane dipeptide isosteres could stabilize a reverse turn. To begin to assess this possibility, a series of cis-substituted cyclopropanes were incorporated as replacements of the Gly(2)-Gly(3) and Phe(4)-Leu(5) dipeptide subunits in Leu-enkephalin (H(2)N-Tyr-Gly-Gly-Phe-Leu-OH), which is believed to bind to opiod receptors in a conformation containing a beta-turn. General methods for the synthesis of the cyclopropane-containing dipeptide isosteres -XaaPsi[COcpCO]Yaa- and -XaaPsi[NHcpNH]Yaa-were developed by a sequence that featured the enantioselective cyclization of allylic diazoacetates catalyzed by the chiral rhodium complexes Rh(2)[(5S)-MEPY](4) and Rh(2)[(5R)-MEPY](4). A useful modification of the Weinreb amidation procedure was applied to the opening of the intermediate lactones with dipeptides, and a novel method for the synthesis of substituted diaminocyclopropanes was also developed. The Leu-enkephalin analogues were tested in a panel of binding and functional assays, and although those derivatives containing cyclopropane replacements of the Gly(2)-Gly(3) exhibited low micromolar affinity for the mu-receptor, analogues containing such replacements for the Phe(4)-Leu(5) subunit did not bind with significant affinity to any of the opioid receptors. These results are discussed.

Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor

“…For example, Leu 5 -enkephalin analogs containing an R-amino squaric acid (54) or a cyclopropane (55) have been synthesized. In addition, cyclic analogs have been prepared to evaluate Leu 5 -enkephalin turn mimetics (56).…”

From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane

“…[31] The inhibitory function of 8 was almoste quipotent to its flexible parentc ompound, while stereoisomer 9 exhibited 300-fold weaker potency,i ndicating that the orientationo ft he phenylg roup upon binding to renin was effectively mimicked by 8 rather than 9.M imicking the b-turn conformation of ap eptide was also demonstrated by the introductiono facyclopropanem oiety to Leu-enkephalin. [32] Mimetic 10 and other similarly designed mimetics, however,s howedm uch lower affinity for opioid receptors than Leu-enkephalin. These findings imply that mimicking the exact conformation required for receptor bindingi sr ather difficult.…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…192 In each of these investigations, we never observed more than a 10-fold enhancement in potency for the constrained analogue over its more flexible control. During this period, we also investigated cyclopropane-derived inhibitors of HIV protease, including 354 and 355, close analogues of the Abbott inhibitor A - 75925 (Figure 18).…”