Browsing Theses and Dissertations School of Pharmacy by Author "Cunningham, Christopher W."
Opioid analgesics with reduced toleranceCunningham, Christopher W.; Coop, Andrew (2008)Morphine is the gold-standard treatment for the management of severe pain. Despite its beneficial analgesic and euphoric effects, the profound development of analgesic tolerance limits its usefulness as a chronic pain therapeutic. Several mechanisms have been proposed, however it is unclear to what extent each contributes to tolerance development. First, the contribution of efflux transporters, such as P-glycoprotein (P-gp), has only recently been investigated, despite being implicated as a potential contributor by numerous studies. Most opioids possess some level of P-gp substrate activity, thus it is imperative to identify and design opioids which bypass this transporter in order to elucidate its effect on tolerance development. Second, it is well established that delta opioid receptor antagonists modulate the tolerance effects of mu receptor agonists, and several groups have attempted to exploit this phenomenon by producing ligands possessing this dual activity profile. To date, few studies have reported highly potent, orally available, small-molecule mu-agonist/delta-antagonist ligands, however recent advances in rational drug design have become crucial tools aiding their development. Combined, to target these mechanisms behind the rapid development of analgesic tolerance, small-molecule ligands have been designed, synthesized, and analyzed both in vitro and in vivo for opioid activity, as well as recognition by P-gp. First, a series of morphine analogs has been synthesized to elucidate the effect of hydrogen bonding of opioids on P-gp substrate activity. This led to the identification of 6-desoxymorphine as a potent opioid agonist with diminished recognition by P-gp. Second, the quantitative conformationally sampled pharmacophore (CSP) model describing delta opioid receptor ligands has been challenged by a structurally-diverse test set and applied toward designing novel, low-efficacy delta opioid ligands. These results facilitated the development of benzylideneoxymorphone (BOM), a small-molecule mu-partial agonist with low efficacy at delta receptors. Finally, based on the results of in silico CSP modeling studies, novel codeine cycloadducts have been synthesized through Diels-Alder condensation of codeine analogs with highly reactive dienes. These products are predicted to be low efficacy delta ligands which would act as probes toward understanding the effect of conformational flexibility on mu/delta receptor efficacy and selectivity. During the course of these procedures, the synthetic process presented unique challenges which were investigated. This has resulted in the optimization of novel synthetic methods which can be utilized for further transformations in opioid chemistry.