Enkephalins agonists

Preliminary data indicate that in the reserpinised rat or MPTP marmoset, the enkephalin agonist (SNC80) reduces PD-like symptoms without causing increased activity, i.e. no trend to dyskinesias. Enadoline, a dynorphin-like kappa opioid agonist also has similar effects in the same models. Whether it would be similar in humans remains to be seen. 

Fig. 1. Structures of two types of opioid agonists where dotted circles surround structural elements common to both compounds (a) Leu-enkephalin and...

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. 

The identification of the morphine receptor spurred an effort in many laboratories to find an endogenous agonist for which that receptor was normally intended. Ultimately, a pair of pentapeptides that bound quite tightly to opiate receptors were isolated from mammalian brains. These peptides, called enkephalins (2, 3), show many of the activities of synthetic opiates in isolated organ systems. They do in fact show analgesic activity when injected directly into the brain. It is thought that lack of activity by other routes of administration is due to their rapid inactivation by peptide cleaving enzymes. 

Matta [37] used the conjoining of Aa residues to obtain the properties of the charge distributions of the proteins Leu- and Met-enkephalin that consist of five residues, in a study of the agonistic activity of the oripavine PEO and morphine. Assembly of the five residues with the required terminal groups resulted in net charges of +0.051 e and -0.043 e, respectively. 

Naloxone precipitates nicotine withdrawal in mice Naloxone induces place aversion in nicotine-dependent rats Naloxone prevents nicotine alleviation of nic. withdrawal Mu and delta agonists reduced mec-precipitated aversion Kappa antagonist suppresses mec.-precipitated aversion P-Endorphin metabolite Gly-Glu blocks aversiveness of mec-precipitated withdrawal Mec precipitates hyperalgesia in nicotine-tolerant rats NAcc Met-enkephalin increased Striatum preproenkephalin mRNA increased... 

The three-dimensional disposition of the nitrogen function to the aromatic ring allows morphine and other analgesics to bind to a pain-reducing receptor in the brain. The terminal tyrosine residue in the natural agonists Met-enkephalin and Leu-enkephalin is mimicked by portions of the morphine structure. 

The recent discovery of a class of peptides, the enkephalins, which act as opiate agonists has led to a number of physical chemical studies aimed at understanding the structure-activity relationships between the enkephalins and the opiates (1 -9). 

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