Date of Award

8-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Advisor

Huffman, John W.

Committee Member

Pennington , William T.

Committee Member

Dieter , R. Karl

Committee Member

Smith, Jr. , Dennis W.

Abstract

The medicinal values of marijuana have often been overshadowed due to the psychotropic, 'recreational' effects it brings about in a user. For hundreds of years the therapeutic uses of cannabis sativa were appreciated, but the inability to control the dosage of the main constituent, and therefore the psychotropic effects, rendered the drug a liability. The elucidation of the structure of this main psychoactive constituent, ∆9-tetrahydrocannabinol (∆9-THC) by Gaoni and Mechoulam in 1964 opened the door to the discovery of a vast array of knowledge about cannabinoids. From the multiple classes of cannabinoids and the ways these compounds interact with the body to the design and synthesis of new cannabinoids based on structure-activity relationships (SAR), the scientific studies into the medicinal effects of marijuana have flourished. There are two main goals of the research presented in this dissertation: To design new cannabinoids that have the potential to become pharmaceutical products with therapeutic effects parallel to ∆9-THC while minimizing the psychoactive effects and to better understand the interactions that these cannabimimetic analogs have with the cannabinoid receptors. This dissertation pursues these goals through the syntheses of two series of cannabimimetic indoles possessing electron-withdrawing substituents and one series of indoles possessing an electron-donating substituent.
Halogenated compounds were the primary focus of the series of indoles possessing electron-withdrawing substituents. These compounds were designed to be selective for the CB2 receptor while also maintaining an affinity for the receptor. Series of both N-alkyl-3-(4-halo-1-naphthoyl)indoles and N-alkyl-3-(8-halo-1-naphthoyl)indoles have been synthesized. These compounds show good affinities for the CB2 receptor and some also have selectivity for CB2.
Huffman, et.al. had previously synthesized four series of N-alkyl-3-(methoxy-1-naphthoyl)indoles which showed either affinity or selectivity for the CB2 receptor depending on the location of the alkoxy group on the naphthoyl ring. A series of N-alkyl-3-(6-methoxy-2-naphthoyl)indoles was synthesized and found to lack any substantial affinity or selectivity for the receptors.

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