Conformational restriction constrained analogs

Tetracyclic compounds in which the C3 side chain is conformationally restricted by linking to either the C2 or the C4 position have been described by Khanolkar et al. [99]. All the tetracyclic compounds had lower CBi and CB2 affinity than the analogous non-constrained compounds (84). The best-tolerated constraint was the southbound constraint in compound (173). 

Peptide derivatives that contain conforma-tionally restricting amino acid units or other conformational constraints were first called conformationally constrained (or restricted) peptide analogs. The use of steric hindrance or cyclization to limit rotational degrees of freedom in biologically active molecules has a long history and was originally applied to non-peptide neurotransmitters (30). Subsequently, it was applied to amino acid substituents and to... 

Conformational restriction has also been used to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett et al. (49) synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin converting enzyme (ACE)inhibitors enalapril (20) and enalaprilat (21) (Fig. 15.9) to characterize torsion angles in the bioactive conformation. Analog (22) was used to constrain the torsion angle psi (T ). Flynn et al. 

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-... 

Conformationally restricted analogs of other low molecular mass agonists have been synthesized or discovered in attempts to characterize the bioactive conformation of the ligand., This field is vast and selected examples of constrained agonist analogs of dopamine (23.10) versus (23.11), GABA (23.12) versus (23.13)-(23.14),2 glutamic acid (23.15) versus (23.16) and (23.17), histamine (23.18) versus (23.19) and (23.20), serotonin (23.21) versus (23.22) that have been discovered by application of this approach are shown in Fig. 23.2. 

MMMS) 200 These techniques turned out to be a valuable tool for the design of conformational constrained analogs of biolc cally active molecules. These compounds, e.g. cyclic peptides 6.203,204) possess an artifically introduced restriction of their conformational flexibility by modifying the peptide backbone. This approach allows a more detailed investigation of the influence of the conformation on biological activity. 

Surely, the introduction of a covalent bond between the aromatic ring of an a-amino acid residue and the peptide backbone has proven to be a useful further conformation restriction. For example, 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) is a cyclic constrained analog of phenylalanine (Figure 5), in which a methylene bridge is placed between the a-nitrogen, and 2 -carbon of the aromatic ring (Kazmierski Hruby, 1988). 

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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