Enkephalin conformations

As mentioned above, the total energy is an index of the conformational stability of peptides in solvent. Table 3-10 gives Eg, A/is, and A t for conformations 1 and 4 of Met-enkephalin. Conformation 1 has intramolecular hydrogen bonds. Conformation 4 is almost fully extended and has no intramolecular hydrogen bonds. Aixs,w, AiJ,s,u, and A s.e denote the solvation free energies in water, methanol, and ethanol, respectively. fi x.W) t,m> t,e denote the total energies in water. 

Figure 13. Plot of met-enkephalin conformation (in stereo). Giobai minimum energy of -50.01 kcal/mol using the RRIGS model for hydration.

The multiple conformational restriction of dermorphin-related tet-rapeptide analogues that was performed represents a rational design of opioid peptidomimetics characterized by a high degree of structural rigid-ification. This is indicated by the fact that the p-selective agonist H-Hat-D-Orn-Aic-Glu-NH2 contains only two freely rotatable bonds, whereas there are 14 freely rotatable bonds in [Leu5]enkephalin. 

DiMaio J, Nguyen TM-D, Lemieux C, Schiller PW. Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogs effect of conformational constraints on opiate receptor selectivity. J Med Chem 1982 25 1432-1438. 

The spin-spin coupling constants [2-4] of the enkephalins in solution can be interpreted in terms of folded conformations resembling that of morphine in the placement of the residues which appear important for biological activity. X-ray crystallography and theoretical calculations (4-9) have also shown that methionine and leucine enkephalin adopt conformations similar to those concluded from NMR studies. Hence it would appear that opioid peptides can topographically resemble the opiates by assuming preferred, folded, conformations. However, earlier studies from this laboratory (TO) have shown that NMR data can be interpreted in terms of a conformationally flexible structure for methionine enkephalin. 

The influence of chain length and side-chain modifications of ACTH-derived peptides on active avoidance behaviour in rats will be discussed. H-Met(02)-Glu-His--Phe-D-Lys-Phe-OH (Org 2766) emerged from these studies as an orally active peptide with an increased potency and selectivity of action. Physico-chemical data (from the literature) on the reference peptide ACTH--(4-10) did not point to a preferred conformation in solution, whereas in the crystalline state an antiparallel 3-pleated sheet structure was found. At the receptor site we suggested an a-helical conformation in which the Phe and Met residues are close together. Additional support for this suggestion came from the behavioural activity of [des-Tyr", Met ]enkephalin and of cyclo--(-Phe-Met-cAhx-), eAhx merely serving as a spacer. 

In the enkephalin studies we began to see how theoretical techniques can be used to generate conformations of related molecules. With the results from GnRH and vasopressin we saw how flexible these molecules are and how the conformational fluctuations and dynamics of these molecules can be studied. We also saw how the relative stabilities of conformations of a molecular fragment can be influenced by conformational constraints of the whole molecule. In the following section we will present some ideas on how these calculations can be incorporated into a conformational based approach to drug design. 

The Z-alkene isostere mimics the cis-amide bond conformation. Its molecular volume and log p values are almost identical to those of the E-isostere (Table 1). Its use in bioactive peptides is very limited, probably because of the synthetic challenge involved. One study reports the migration of the double bond to the a,(3-position in an enkephalin analogue. 4 The Z-alkene in the Alat t[Z, CH=CH]Pro dipeptide isostere, however, was reported to be stable towards isomerization.1 1X1 orf/to-Substituted aromatic or tetrazole rings have been used more frequently as ds-amide bond mimics. 

More recently, we have been addressing a problem described previously concerning the relationship between morphine and enkephalin. The inherent mobility of the enkephalin framework, its rapid degradation in vivo/1341 and the existence of multiple receptor sub-types 135 136] have hampered the assessment of its bioactive conformations. Conformationally... 

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