An SAR study on the Dmt-substituted enkephalin-like tetrapeptide with a N-phenyl-N-piperidin-4-yl propionamide moiety at C-terminal was performed, and has resulted in highly potent ligands at μ and δ opioid receptors. In general, ligands with the substitution of D-Nle 2 and halogenation of the aromatic ring of Phe 4 showed highly increased opioid activities. Ligand 6 with good biological activities in vitro demonstrated potent in vivo antihyperalgesic and antiallodynic effects in the tailflick assay.

It has been known that co-administration of morphine with either cholecystokinin(CCK) receptor or melanocortin (MC) receptor antagonists enhance morphine's analgesic efficacy by reducing serious side effects such as tolerance and addiction.1 -4 Considering these synergistic effects, we have designed trivalent ligands in which all three different pharmacophores for opioid, CCK, and MC receptors are combined in such a way as to conserve their own topographical pharmacophore structures. These ligands, excluding the cyclic compound, were synthesized by solid phase synthesis using Rink-amide resin under microwave assistance in very high yields. These trivalent ligands bind to their respective receptors well demonstrating that the topographical pharmacophore structures for the three receptors were retained for receptor binding. Ligand 10 was a lead compound to show the best biological activities at all three receptors.Neuropathic pain which is induced by injury of nervous system and characterized by hyperalgesia and allodynia is particularly difficult to treat because of its complicated developmental mechanism. The most commonly used opioids such as morphine have little effect on such pain and possess a high risk of addiction, constipation, and other toxicities. Repeated administration of morphine results in enhanced levels of substance P, a transmitter of pain signals. This induces increased pain that require a higher dose of pain-relief and thus produces tolerance and intense physical dependence.5 Cholecystokinin (CCK) acting at CCK receptors is known to give an anti-opioid effect and as a result, causes an increase of pain by inhibiting the opioid response.6 -7 Other studies have shown further that agonists for melanocortin (MC) receptors, mainly subtype MC-4R, produce an increase in response to pain stimuli.8 -9 Therefore we have postulated that inappropriate interactions of opioid ligands with endogenous anti-opioid receptors such as CCK are one of the major problems to be addressed in treating neuropathic pain states.10 In previous studies, we have examined a new approach for designing drugs that will be effective in these pain states, and have illustrated the potential for this approach with examples of designing in single molecule © 2010 Elsevier Ltd. All rights reserved. * Corresponding author. Tel: 1-520-621-6332, Fax: 1-520-621-8407, hruby@u.arizona.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Fig. 1). To explore the SAR of opioid with CCK and MC pharmacophores, modifications were performed mainly in the opioid pharmacophore (Fig. 2). NIH Public Acce...