Peripherally acting enkephalin analogs. 1. Polar pentapeptides

Abstract

The design, synthesis, and biological activity of a series of highly polar enkephalin-related pentapeptides are reported. These analogues incorporate structural features that exclude them from the central nervous system and thereby restrict their action to peripherally located receptors. Hydrophilic analogues were obtained by introduction of polar D-amino acid residues at position 2 and, in certain cases, by conversion of the N-terminal amino group of the Tyr residue to a guanidino function. The peptides were synthesized by classical solution methods. All compounds demonstrated in vitro opioid activity in the GPI and all were shown to possess antinociceptive activity in chemically induced writhing models. The analgesic effects were shown to be predominantly peripherally mediated by antagonism of antinociception with the peripheral antagonist N-methylnalorphine. Comparative data obtained in writhing and hot-plate tests were also supportive of a peripheral mode of action. Compound 13a, L-tyrosyl-D-arginylglycyl-L-4-nitrophenylalanyl-L-prolinamide (BW 443C), was identified as having a favorable pharmacological profile, indicating a high level of peripheral selectivity, and worthy of further investigation.

The cardiovascular and central nervous system effects in the human of U-62066E

“…Metkephamid therefore also appears to be acting centrally to lower blood pressure. Contrary to the above findings, intravenous infusion of a novel enkephalin analogue, 443 C81 (Tyr-D-Arg-Gly-Phe (4NO2)-Pro-NH2) which does not penetrate the CNS [8] in healthy volunteers decreased blood pressure without compensatory tachycardia and also reduced venous tone, forearm vascular resistance and systemic vascular resistance [9,10] suggesting some peripheral action of opioids. Naloxone prevents the fall in blood pressure which occurs during sleep and it has been inferred that endogenous opioids have a physiological role in the blood pressure changes occurring during sleep but that this role may be indirect [11].…”

“…Dynorphin [1][2][3][4][5][6][7][8][9][10][11][12][13] and D'Ala 2, D-LeuS-enkephalin also reduced plasma noradrenaline concentration and blood pressure in pithed rabbits [28] and ethylketocyclazocine was shown to inhibit the release of noradrenaline from sympathetic neurones innervating the sinus node of the rabbit [29].…”

Tabernaemontana catharinensis ethyl acetate fraction presents antinociceptive activity without causing toxicological effects in mice

“…In this model of inflammatory pain, occurs the release of several pro-inflammatory mediators such as prostaglandins, bradykinin, substance P, and cytokines as interleukins (IL)-1, -8 and tumor necrosis factor (Rossato et al, 2014) and it is sensitive to non-steroidal anti-inflammatory drugs (NSAIDs) such as sodium diclofenac (Melo et al, 2013). Moreover, this nociceptive test is used to detect antinociceptive activity of drugs acting on the peripheral, spinal and supraspinal levels (Hardy et al, 1988). We also investigated the effects of Eta in the tail-immersion test, which is used to detect antinociceptive activity of drugs acting on central nervous system such as opioids analgesics (Vanderah et al, 2008).…”

L’administration intradermique de sufentanil n’améliore pas l’anesthésie locale induite par la lidocaïne

“…10,[15][16][17] Inflammation not only disturbs the neural barrier but also may cause increased de novo synthesis and peripherally directed axonal transport of opiate receptors, 18 as well as conformational changes. 19 In experimental canine arthritis, the density of specific opioid radioligand binding was markedly enhanced in homogenates prepared from the joint in which inflammation was induced with oleyl alcohol and sterile peanut oil injection.…”