Logan Abbott proposes modifying the C17 position of the kappa opioid receptor agonist salvinorin A to synthesize novel analogs. Salvinorin A is a potent and selective KOR agonist but has poor solubility. Previous work showed modifying C17 maintains activity. Abbott will synthesize 5 analogs by converting salvinorin A's acetol to an azide then to an amide through traceless ligation. The goal is identifying a potent KOR agonist to treat drug abuse by targeting receptors other than mu opioid receptors targeted by current therapies. Abbott has experience in the lab synthesizing earlier C17 analogs and will assess compounds' pharmacological activity.

1. Undergraduate Research Award Application, Spring 2015
Synthesis of Pharmacologically Active Analogs of Salvinorin A
Proposal by Logan Abbott
Mentored by Dr. Thomas E. Prisinzano
Abstract: Addiction is a complex disorder of the brain in which we see a developing
adaptation upon subsequent exposures to drugs of abuse. A fundamental aspect of drug
abuse involves the body’s reward system, or its response to pleasurable stimuli from
drugs of abuse. One notable system involved within the body’s natural reward process is
the opioid system. The opioid system, including the mu (MOR), delta (DOR), and kappa
(KOR) opioid receptors interacting with a large family of endogenous opioid peptides, is
broadly distributed along the neurocircuitry of addiction2
. As a result of its extensive
distribution, the opioid system is a popular target for the treatment of drug abuse.
Salvinorin A, the major active component in the hallucinogen Salvia divinorum, is a
potent and selective agonist at the KOR. As a natural product, salvinorin A provides a
unique but fertile opportunity for the synthesis of active analogs with the potential to
serve as novel therapies in the treatment of drug abuse.
Background and Introduction:
The total cost of drug abuse in the United States is estimated to exceed $600 billion annually. This
estimation includes loss of productivity and both health and crime-related costs. This includes
approximately $193 billion for illicit drugs and $235 billion for alcohol1
. With such staggering numbers
concerning the cost of drug abuse, researchers have turned toward finding an answer. For example,
Naloxone, Methadone, and Buprenorphine serve as treatment options currently available for opioid abuse.
As therapies for opioid abuse, these agents all act at opioid receptors, namely, the Mu opioid receptor
(MOR). The MOR is essential to mediating the rewarding properties of opiates, as well as non-opioid
drugs of abuse and natural stimuli2
. In addition to MOR, the human body is also known to possess both
Kappa opioid receptors (KOR) and Delta opioid receptors (DOR). Together, the family of opioid
receptors has shown the ability to regulate the reward system while also contributing to cognitive
dysfunction that predisposes individuals to the development of addiction.
In addiction research, KOR agonism is definitely considered a major anti-reward system,
producing dysphoric effects and antagonizing rewarding effects of drugs of abuse and social stimuli2
.
However, as previously shown, the current treatment approaches for drug abuse all target the MOR.
Taken together, this information has led to the investigation of other opioid receptors, specifically the
KOR, as potential pharmacologic targets in the treatment of drug abuse. Due to the growing interest in the
KOR as a therapeutic target, the neoclerodane diterpene salvinorin A has surfaced as a candidate for
researching the KOR and its role in the drug reward pathway.
First and foremost, salvinorin A offers an enticing compound for research because it acts as a
potent and selective agonist at the KOR with a rapid onset and short duration of action. In other words, as
a potential therapeutic agent, one can recognize the favorable pharmacodynamic parameters this
compound possesses, while exerting its effects at a site that differs from existing treatment options.
Further, salvinorin A is an investigational candidate because it serves as an atypical opioid. While
salvinorin A is a potent and selective KOR agonist, it does not structurally resemble many of the known
non-peptide opioid receptor ligands (See Figure 1). The most astonishing of these structural differences is
the lack of a basic nitrogen atom in the chemical structure of salvinorin A. Up until the discovery of
salvinorin A, the presence of a basic nitrogen atom was proposed to be a necessary structural requirement
for opioid receptor affinity4
. Conversely, salvinorin A also possesses many undesirable pharmacokinetic
properties. Salvinorin A, as suggested by its chemical structure, is a poorly water-soluble molecule. As a
compound with a poor solubility profile, it is reasonable to expect the compound to be poorly bioavailable
when orally administered. This is evidenced by the fact that salvinorin A has a historical niche in Mexican
culture as a smoked agent used in divination rituals. Due to its poor water solubility and bioavailability,
one can deduce that salvinorin A will require extensive formulation changes in order to achieve any

2. Undergraduate Research Award Application, Spring 2015
potential therapeutic benefit. In summation, as a compound with both positive and negative structural
characteristics that culminate its pharmacological profile, the nonalkaloid salvinorin A offers a potential
scaffold for chemical modification to allow further investigation into the therapeutic potential of this
agent as a treatment for drug abuse.
Figure 1: Chemical Structures of Various Opioids
Approach and Timeline:
Upon choosing salvinorin A as the compound of interest, I will investigate the C17 position of the
compound as my project over the course of the upcoming semester. Previous investigation has shown that
the C17 lactone can be reduced to the lactol without a significant loss of KOR activity3
. Further,
preliminary results from the Prisinzano laboratory have shown that modification at the C17 position to
form the acetol again maintains activity with one hundred percent efficacy. Conversely, if we modify the
chemical structure at the C17 position by adding an allyl group off of C17, we see a modest reduction in
activity. This indicates that there may be some hydrogen bonding interactions with the KOR active site
and the C17 position that are important to maintain for activity and potency. The synthesis of these
compounds begins with the selective reduction of salvinorin A to the lactol compound, followed by the
acetylation of the lactol to produce the acetol compound (See Scheme 1). Further derivation of the acetol
can be accomplished in the presence of a Lewis acid and a silyl-protected nucleophile (conditions for the
formation of the allyl compound are shown below). Thus far, this step has proven fairly robust to
accommodate a wide variety of nucleophiles.
Scheme 1: Synthetic Scheme of C17-substituted analogs
HO
O
HO
N
Morphine
H
O
O
O
O
H
CO2Me
H
O
O
N
N
O
Fentanyl
Salvinorin A
O
OH
O
O
H
CO2Me
H
O
O
O
O
O
O
H
CO2Me
H
O
O
O
O
O
O
H
CO2Me
H
O
O
O
OH
O
O
H
CO2Me
H
HO
Salvinorin A
O
SVA Lactol SVB Lactol
SVA Acetol
OO
O
H
CO2Me
H
O
O
DIBAL, THF, -78°C
Mixture of SVA and
SVB Lactols,
controlled by DIBAL
equivalents
+
(mixture of Lactols)
Ac2O, DMAP
DCM, rt
85%
Allyl TMS
BF3
.Et2O
DCM, -78°C
C17-substituted SVA analogs

3. Undergraduate Research Award Application, Spring 2015
The specific aim of my research project is to modify the C17-lactone of the KOR agonist
salvinorin A through semi-synthetic modifications in order to synthesize compounds that retain activity at
the KOR. My goal for this semester-long project is to synthesize five compounds, following the synthetic
Scheme 2, that retain pharmacologic activity. The proposed analogs have various groups appended to a
C17 amide. We chose to investigate a C17 amide due to the previously mentioned possibility that
hydrogen-bonding may play a role in affecting potency at the KOR. As the ultimate goal of this project is
to develop KOR agonists, I will then use my training in pharmacologic assays to assess these analogs for
KOR activity with the intent of identifying a potent KOR agonist.
To achieve these goals, I will begin my project by utilizing the previously optimized reactions to
convert salvinorin A into the acetol compound. With the acetol synthesized, I will then begin to make the
test bioisosteres that I have proposed. The acetol will be converted into the azide through treatment with
TMSN3 in CH2Cl2 in the presence of BF3
.
Et2O5
. While this reaction is the first proposed reaction that has
not already been optimized, I anticipate that it will be successful due to its similarity to the allylation
reaction shown in Scheme 2, as well as its well documented precedence in the literature. Following
successful conversion to the azide analog, I will synthesize the amide analog using a Traceless Staudinger
reaction6
as outlined in Scheme 2. I will then test the pharmacological activity of the analogs that I make;
the Prisinzano laboratory is already equipped to evaluate KOR activity in vitro.
Scheme 2: Synthesis of Proposed Amides
While I anticipate the synthesis of these compounds to be successful based upon literature
protocol and the preliminary reactions that have already been completed successfully in the Prisinzano
laboratory, there are alternative methods for both proposed reactions. The fundamental conversion of an
acetol to azide is a highly precedented reaction. The formation of the amide bond from the azide analog
can be performed in an alternative fashion via reaction of the azide in the presence of a thio acid reagent7
.
The C17 position of the potent and natural hallucinogen salvinorin A is a relatively unexplored
functional modification site. While it is accepted that the carbonyl lactone substituent retains activity
upon being reduced to the lactol, the impact of further structural modification represents a relatively novel
structure-activity relationship. Moreover, little research has taken place toward investigating the amount
and nature of the requirements to retain activity at this site. Throughout the span of my proposed project, I
will be contributing to the understanding of the structure-activity relationships by synthesizing
bioisosteres of salvinorin A that differ only at the C17 position of the compound. The selective
modification of the compound will add new insight to an underexplored area of the compound that has a
desirable structural activity profile for possible employment as a therapeutic option.
Significance to Applicant:
This award is significant to me as an applicant because it would allow me an opportunity to conduct
contemporary drug discovery research. Further, I would be able to explore many of the concepts that I
have been introduced to as a pharmacy student in a firsthand setting. As previously mentioned, I am
currently a 3rd
year student in the School of Pharmacy at the University of Kansas, and upon completing
my PharmD, I plan to attend graduate school in order to receive my PhD in medicinal chemistry. The
OO
O
H
CO2Me
H
O
O
N3
O
O
O
O
H
CO2Me
H
O
O
O
SVA Acetol
TMSN3
BF3
.Et2O
DCM
PPh2
O R
O
C17-Azide
OO
O
H
CO2Me
H
O
O
N
H
R
O
DMA/DPU;
then H2O
70°C
Proposed Amide Analogs

4. Undergraduate Research Award Application, Spring 2015
privilege to collaborate with a first-class mentor in Dr. Prisinzano on an involved research project will be
beneficial for my graduate school aspirations.
Applicant Qualifications:
As a pharmacy student, I had the opportunity to take an elective in undergraduate research as a part of my
curriculum. I chose to work in Dr. Prisinzano’s medicinal chemistry laboratory, where I have been
performing research for the past year. In carrying out my research in the Prisinzano laboratory over the
past year, I have already been trained in many organic chemistry techniques through the use of equipment
such as rotary evaporators, NMR spectroscopy, and mass spectrometry. I am also proficient in column
chromatography, high performance liquid chromatography, and purification techniques. Moreover, I have
had the opportunity to be involved in some aspect of this C17 site-modification project, including the first
two steps in my proposed scheme—the reduction and the acetylation. My familiarity with both the
chemistry and the technique involving my proposed research project provides a foundation from which to
develop my project over the course of the semester.
References:
1
"DrugFacts: Understanding Drug Abuse and Addiction." National Institute on Health. National Institute
on Drug Abuse (NIDA), 1 Nov. 2012. Web. 27 Oct. 2014.
2
Lutz P-E, Kieffer BL. “The multiple facets of opioid receptor function: implications for addiction.”
Current Opinion in Neurobiology, 2013. http://dx.doi.org/10.1016/jconb.2013.02.005.
3
Saylor, Rachel and Prisinzano, Thomas E. “Synthesis of C12- and C17- Modified Analogs of Salvinorin
A as Kappa Opioid Receptor Agonists.” University of Kansas, Lawrence, KS 66045. 2014.
4
Prisinzano, Thomas E. “Neoclerodanes as Atypical Opioid Receptor Ligands.” Journal of Medicinal
Chemistry. 2013, 56, 3435-3443. https://dx.doi.org/10.1021/jm400388u.
5
Guo, Zhongwu and Wu, Qiuye. “Synthesis and Antifungal Activities of Glycosylated Derivatives of the
Cyclic Peptide Fungicide Caspofungin.” ChemMedChem. 2012, 7, 1496-1503.
https://dx.doi.org/10.1002/cmdc.201200214.
6
Bernardi, Anna. “Stereoselective Synthesis of a- and b-Glycofuranosyl Amides by Traceless Ligation of
Glycofuranosyl Azides.” Chem. Eur. J. 2012, 18, 6895-6906.
https://dx.doi.org/10.1002/chem.201200309.
7
Williams, Lawrence J. “The Reaction of Thio Acids with Azides: A New Mechanism and New Synthetic
Applications.” J. Am. Chem. Soc. 2003, 125, 7754-7755. https://dx.doi.org/10.1021/ja0294919.