Enkephalin analogs conformationally restricted

The work of Veber et al. established that valuable information about the bioactive conformation of a flexible peptide could be obtained by applying the principles of conformational restriction, and several additional examples soon were reported that followed this strategy. Conformationally restricted enkephalin analogs, e.g., 02-13), were formed by cyclizing between positions 2 and 5 of enkephalins (4a-b) (39). Cyclization of a-mela-notropin (14) gave the unusually active analog... 

Conformationally Constrained Analogs. Local restriction of conformational freedom can be accomplished by incorporating conformationally constrained amino acids (see Refs. 679,680 for reviews). In the case of the enkephalins, incorporation of 2-amino-6-hy-droxy-2-tetralincarboxylic acid (Hat, Fig. 7.43) in place of Tyr in [Leu ]enkephalin methyl ester results in a /u,-selective compound [IC50 ratio (MVD/GPI) = 5.11, whereas the analog containing 2-hydroxy-5-hydroxy-2-indane-carboj rlic acid (Hai) is virtually inactive (681). Incorporation of 2, 6 -dimethyltyrosine (Dmt,... 

Conformationally Constrained Analogs. Local restriction of conformation in the linear enkephalins has included incorporation of dehydroamino acids [e.g., dehydrophenylalanine (APhe, Fig. 7.43)] and cyclopropyl-methylphenylalanine (VPhe) into the peptides (see Ref 704 for a review). In the case of the dehydrophenylalanine (APhe ) derivatives of [D-Ala, Leu ]enkephalin, the Z isomer exhib-... 

However, while the Indane analog shows considerably less activity in the guinea pig ileum and mouse vas deferens assays chan [Leu ]enkephalln, the tetralin analog is more active in the guinea pig ileum (p-receptor) assay and much less active in the mouse vas deferens (6-receptor) assay than [leu ]enkephalin. Implying an Increase of receptor specificity by this conformational restriction. The use of dehydro amino acids to Induce rigidity and increase hydrophoblclty of the enkephalins has resulted in the u-selective [AAla , Leu ]enkephalln and the 6-selective [D -Ala ,... 

Conformational Restrictions for Receptor Specific Analogs. Development of d Receptor Selective Enkephalins... 

The enkephalins have been the most extensively modified of the opioid peptides, and thousands of analogs of these pentapeptides have been prepared (see Refs. 653-658 for reviews). The naturally occurring enkephalins exhibit some selectivity for 8 receptors (see Table 7.9), but these peptides are rapidly degraded by a variety of peptidases (see Section 6.8 below). Therefore one major goal of structural modification of these small peptides has been to increase metabolic stability. Depending on the nature of the modifications made, both jLt- and S-selective enkephalin derivatives have been prepared (enkephalin derivatives generally have very low affinity for k opioid receptors). These derivatives have included both linear peptides and conformationally constrained derivatives. Conformational constraints have included cyclizations between residues in the peptide chain and local constraints by incorporation of an amino acid whose side-chain conformation is restricted. 

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