Met-enkephalin and morphine

The design of a peptoid library using non-peptoid leads such as met-enkephalin and morphine represents an important practical instance of a rational... 

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 work of Vaught et a/.,<215) in which natural enkephalins are shown to have much lower affinities for /x-sites than generally believed, and evidence presented of Leu-enkephalin potentiating and Met-enkephalin attenuating morphine analgesia in mice are discussed in Chapter 13 (p. 490). 

There are three families of endogenous opioid neuropeptides that interact with opioid receptors enkephalins, endorphins and d)morphins (Carvey 1998). These neuropeptides have varying affinities for the three types of opioid receptors, though none binds exclusively to only one receptor type (Meunier et al 1995). Beta-endorphin shows equal activity at x and 8 opioid receptors with lesser affinity for k receptors. Met-enkephalin and leu-enkephalin have high affinity for 8 receptors, their affinity for p, receptors is one-tenth of that for 8 receptors and they have negligible affinity for k receptors. Dynorphdns A and B have high affinity for K receptors but also bind to x and 8 receptors (Corbett et al 1993). 

Met-enkephalin and leu-enkephalin belong to a group of peptides called the opioid peptides, found predominantly in nerve tissue cells. Opioid peptides are molecules that relieve pain (a protective mechanism in animals that warns of tissue damage) and produce pleasant sensations. They were discovered after researchers suspected that the physiological effects of opiate drugs such as morphine resulted from their binding to nerve cell receptors for endogenous molecules. Leu-enkephalin and met-enkephalin are pentapeptides that differ only in their C-terminal amino acid residues. Substance P and bradykinin stimulate the perception of pain, an effect opposed by the opioid peptides. 

Both peptides behave as agonists and inhibit opiate receptor binding, with affinities comparable to the affinity of morphine. The effects of met-enkephalin and leu-enkephalin are reversed by naloxone. Three distinct families of peptides... 

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. 

Related peptides with terminal Phe reduced to phenylalaninol (Pheol) or replaced by N-phenethylamide also show potencies of the morphine order in the GPI assay. The derivative Tyr-D-Met(0)-Gly-N-methylphenethylamide, termed syndyphalin, is about as potent as morphine in mice after sc injection by MTF and WR tests with selectivity for p,-sites.<76 77,194) A Reckitt and Colman group(78) has described some similar derivatives 8 based on the protected tetrapeptide Tyr-D-Ala-Gly-MePhe the GPI and MVD potencies reveal their potent -receptor activities. The compound terminated by a reduced Gly residue (DAGO) is in fact one of the most selective p,-ligands available (see p. 356). All three peptides 8 were much more stable to brain and plasma enzymes than Leu-enkephalin, and two had activities close to or better than that of morphine in a rat in vivo test. 

Fig 10 1 The agonist activities of various compounds in the mouse vas deferens and guinea pig ileum and their potencies to inhibit 3H-Leu-enkephalm and [3H]naloxone binding in homogenates of guinea pig brain (pH 7 4 at 0°C, no Na+, 150 min) The numbers on the absiccsa indicate the amino acid sequence of /3 -lipoprotein, Leu, leu-enkephalin and Mo, morphine All peptides are synthetic (61-91, ovine /3-endorphin, 61-65, met-enkephahn and leu-enkephalin)... 

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