A series of morphinan-based compounds inspired by the semi-synthetic opioid metopon have been synthesized. An expedient route from (-)-codeine to the key intermediate, 6,7-a-epoxide has been developed giving access to enantio-enriched analogs. Classical diaxial opening of the a-epoxide has allowed for introduction of b-substituents at C7, emulating the 5b-methyl group in metopon. Several analogs exhibited dual agonist activity at the m- andd-receptors while lacking significant affinity for k-receptors, fulfilling a requirement for an opioid with a diminished side-effect profile. Additionally, a collective synthesis of 8,14-dihydronorsalutaridine, 8,14-dihydrosalutaridine, norisosinomenine and isosinomenine is reported. The strategy employed provides direct access to the correct oxidation level of the products by avoiding the biomimetic strategy of o, p-phenolic oxidative coupling. The combination of an organocatalyst guanidine superbase, a tertiary amine base and a dehydrating agent was found necessary for the successful Henry-Michael-dehydration cascade to form the phenanthrene motif. The requirement for an efficient and selective aliphatic nitro reduction could be achieved only under heterogeneous transfer-hydrogenation conditions. Conversion of 8,14-dihydrosalutaridine into salutaridine by oxidation of the C8-C14 into a double bond would allow for subsequent biomimetic transformation of the resultant dienone structures consecutively into thebaine and codeine. The combination of these routes provide a highly practical racemic synthesis of certain 8,14-dihydromorphinandienone alkaloids, and by extension, of thebaine and codeine. / text

Many factors present during the perioperative period render patients susceptible in developing myocardial ischaemia reperfusion injury. Various mode of conditioning the heart against this type of injury has been discovered in animal models and involve powerful innate pathways that enhance cellular survival. These may be harnessed by applying a trigger either immediately before (preconditioning) or after (postconditioning) the lethal ischaemic injury, by physical or pharmacological means. Morphine was the first clinically used opioid shown to be cardioprotective but the intravenous dose required limited its use clinically. Remifentanil, an ultra-short acting opioid, was later also shown to be cardioprotective. A better understanding of how these opioids can protect the heart may enable the rational design of clinical regimens that best protect patients. The purpose of this thesis is to demonstrate and elucidate how these two agents provide cardiac protection. I first demonstrated the clinical efficacy of remifentanil preconditioning in reducing the release CKMB, cardiac troponin I, heart type fatty acid binding protein and ischaemia modified albumin following cardiopulmonary bypass. As opioids cannot be omitted completely from patients undergoing cardiac surgery due to ethical considerations, I then used a well-established animal model of ischaemia reperfusion injury to complete the remainder of the studies. I demonstrated that remifentanil postconditioning was also effective in reducing myocardial infarct size, an effect mediated through the activation of kappa and delta opioid receptor subtypes, and in part triggered at the level of the myocardium. I then confirmed previous findings showing the efficacy of intrathecal morphine preconditioning using clinically relevant doses. In addition, I demonstrated that all three opioid receptor subtypes were involved. This effect was comparable to that achievable by classical ischaemic or intravenous morphine preconditioning and is mediated by central but not peripheral opioid receptor activation. Intrathecal morphine reduces the degree of myocardial apoptosis, alters the phosphorylation of Akt and the expression of endothelial nitric oxide synthatase and opens the potassium ATP channels. It also involves spinal adenosine receptors, similar to spinal morphine mediated analgesia. Intrathecal morphine preconditioning can be abolished by the interruption of autonomic nervous system function and blockade of calcitonin gene related peptide (CGRP) and bradykinin receptors. Intrathecal morphine postconditioning also has an infarct sparing effect. It also involves the activation of central opioid receptors and peripheral adenosine and CGRP receptors. Finally I demonstrated a pivotal role of central opioid receptor in remote preconditioning by showing that selective blockade of these receptors abolished the protective effects of remote but not classical ischaemic preconditioning. Cumulatively, these results demonstrated the versatility of opioid mediated cardioprotection using morphine or remifentanil and the pivotal role of central opioid receptors in cardioprotection and revealed some of the mechanisms underlying these benefits. Not only does intrathecal morphine provide analgesia, it also generates signals that are transmitted through the autonomic nervous system resulting in changes in cellular function in the heart. This point to the possibility of a relationship between an organism’s intrinsic response to pain and the triggering of an innate organ protective response to ischaemia. / published_or_final_version / Anaesthesiology / Master / Doctor of Medicine

No description available.

Thesis (M.S.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on January 4, 2008) Includes bibliographical references.

Thesis (Ph.D.)--Tufts University, 2005. / Adviser: Robin B. Kanarek. Submitted to the Dept. of Psychology. Includes bibliographical references (leaves 79-91). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Thesis (Ph.D.)--University of Melbourne, Dept. of Chemistry, 2006. / Typescript. Includes bibliographical references (leaves 245-289).

Thesis (Ph.D.)--Victoria University of Wellington, 2008. / Includes bibliographical references.

Thesis (Ph. D.)--University of Michigan, 1997. / Includes bibliographical references.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2002. / Includes bibliographical references (leaves 83-103). Also available in electronic version. Access restricted to campus users.

Thesis (Ph. D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaves 128-149).