Chapter 191 - Opioid-Substance P Chimeric Peptides

Abstract

Chimerization of tachykinin and opioid pharmacophores offers a new opportunity for analgesic development. The complexities of such design are illustrated by the analgesic efficacy of chimeras that combine pharmacophores with opioid activity and substance P activity, as well as those that combine opioid agonist and substance P antagonist moieties. Although the interaction between substance P and opioid neural systems is more complex than a simple one-way inhibition, the relative balance of activities between tachykinin and opioid pharmacophores will generally determine the net effect of the chimeric molecule as pro-nociceptive, antinociceptive, or neutral. The majority of neurophysiological and pharmacological studies have indicated that substance P and opioid systems are functionally antagonistic in the mediation of nociception and antinociception in vivo. Thus, the simultaneous blockade of substance P receptors and activation of opioid receptors seems quite a reasonable approach to the construction of chimeric peptides. Hybridization of an opioid agonist with a substance P antagonist results in compounds with a synergistic antinociceptive interaction of both hybridized components. The hybridization of opioid agonists with substance P agonists may result in effective analgesics without apparent opioid tolerance during chronic application.