This report describes the synthesis, chemical derivation, and pharmacological and behavioral characterization of several unique classes of opioid receptor modulators. In chapter one, a general overview of opioid receptor history, signaling biology, and therapeutic applications is provided. Also reviewed are several topics of high current interest, including, biased signaling, opioid receptor splice variants/heteromers, and applications of opioid modulators in the treatment of mood disorders. This introduction aims to frame the work that follows, and emphasize to the reader the untapped potential of the opioid receptor system, particularly in the realm of therapeutics development.
Chapter two discusses the development of several new C-H activation reactions to provide rapid access to the core molecular scaffold of alkaloids from Tabernanthe iboga. The methods described permit the expedient construction of structurally diverse ibogamine analogs via a modular approach. In chapter three, this work is extended by applying the new reaction methodologies to explore a novel class of oxaibogamine analogs, which act as opioid receptor agonists and antagonists. The thorough exploration of structure-activity relationships within this skeleton is described, along with the pharmacological characterization of several select analogs as biased agonists at both the kappa- and mu-opioid receptors. This section concludes with a discussion of potential therapeutic applications for the synthesized compounds as new analgesics and antidepressants, and future goals and plans for this structural class.
In chapter four, the isolation and pharmacological study of several alkaloids of Mitragyna speciosa is presented. Mitragynine, the primary natural alkaloid in this plant, is isolated, along with several naturally occurring analogs, and the modulatory activity of these compounds at the opioid receptors is fully characterized. Further, preliminary results are presented suggesting activity of these alkaloids at several other classes of central nervous system targets, including serotonin and adrenergic receptors. Also discussed are the preparations of semi-synthetic and fully synthetic mitragynine derivatives, including a total synthesis of mitragynine itself. These novel analogs are applied to explore key structure-activity relationships in this unusual opioid-active scaffold. Again, potential applications of Mitragyna alkaloid analogs in the treatment of pain and depression are discussed.
In the final chapter, I describe our discovery that tianeptine, a clinically used atypical antidepressant of previously unknown mechanism of action, acts as an agonist of both the mu- and delta-opioid receptors. Activation of the mu-opioid receptor is thus proposed as the initial molecular-level event responsible for eliciting the beneficial therapeutic effects of this agent. This hypothesis is integrated with the large body of literature describing this compound, and mechanistic theories connecting the opioid activity of tianeptine to previous observations are described, with a particular emphasis on indirect modulation of glutamate signaling. Behavioral studies in mice employing both genetic knockout and pharmacological inhibition are then used to confirm the involvement of the opioid receptors in tianeptine's mechanism of action. Also described are thorough explorations of opioid structure-activity relationships within the tianeptine scaffold, and the design and synthesis of novel analogs having improved pharmacokinetic properties. It is hoped that these derivatives may one day serve as new therapeutic options for patients suffering from treatment-resistant depression.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/D8V1242F |
| Date | January 2015 |
| Creators | Kruegel, Andrew Carry |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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