5 research outputs found
The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments
This work is licensed under a Creative Commons Attribution 4.0 International License.(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.NIDA grant P30 DA13429NIDA grant DA039997NIDA grant DA018151NIDA grant DA035857NIDA grant DA047574NIH Intramural Research Programs of the National Institute on Drug AbuseNational Institute of Alcohol Abuse and AlcoholismNIH Intramural Research Programs of the National Institute on Drug AbuseNIH Intramural Research Program through the Center for Information TechnologyNIH Intramural Research Programs of the National Institute on Drug Abus
Semisynthesis and Kappa-Opioid Receptor Activity of Derivatives of Columbin, a Furanolactone Diterpene
Columbin (<b>1</b>) is a furanolactone
diterpene isolated
from the roots of <i>Jateorhiza</i> and <i>Tinospora</i> species. These species generally grow in Asia and Africa and have
been used in folk medicine for their apparent analgesic and antipyretic
activities. Columbin (<b>1</b>) is of particular interest due
to its structural similarity to the known kappa-opioid receptor (KOR)
agonist salvinorin A. Given that the KOR is of interest in the study
of many serious diseases, such as anxiety, depression, and drug addiction,
obtaining natural or semisynthetic molecules with KOR activity recently
has gained much interest. For this reason, in the present study, derivatives
of <b>1</b> were designed and synthesized using known structure–activity
relationships of salvinorin A at KORs. The structures of the columbin
analogues prepared were elucidated by NMR spectroscopy and mass spectroscopy,
and their KOR activity was investigated in vitro by inhibition of
forskolin-induced cAMP accumulation. Slight improvements in KOR activity
were observed in columbin derivatives over their parent compound.
However, despite the structural similarities to salvinorin A, neither
columbin (<b>1</b>) nor its derivatives were potent KOR ligands.
This work represents not only the first evaluation of columbin (<b>1</b>) at the KOR but also one of the first works to explore synthetic
strategies that are tolerated on the columbin core
Addressing Structural Flexibility at the A‑Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability
Previous
structure–activity studies on the neoclerodane diterpenoid
salvinorin A have demonstrated the importance of the acetoxy functionality
on the A-ring in its activity as a κ-opioid receptor agonist.
Few studies have focused on understanding the role of conformation
in these interactions. Herein we describe the synthesis and evaluation
of both flexible and conformationally restricted compounds derived
from salvinorin A. One such compound, spirobutyrolactone <b>14</b>, was synthesized in a single step from salvinorin B and had similar
potency and selectivity to salvinorin A (EC<sub>50</sub> = 0.6 ±
0.2 nM at κ; >10000 nM at μ and δ). Microsomal
stability studies demonstrated that <b>14</b> was more metabolically
resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory
properties revealed similar in vivo effects between <b>14</b> and salvinorin A. To our knowledge, this study represents the first
example of bioisosteric replacement of an acetate group by a spirobutyrolactone
to produce a metabolically resistant derivative
Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability
Opioids
are widely used to treat millions suffering from pain,
but their analgesic utility is limited due to associated side effects.
Herein we report the development and evaluation of a chemical probe
exhibiting analgesia and reduced opioid-induced side effects. This
compound, kurkinorin (<b>5</b>), is a potent and selective μ-opioid
receptor (MOR) agonist (EC<sub>50</sub> = 1.2 nM, >8000 μ/κ
selectivity). <b>5</b> is a biased activator of MOR-induced
G-protein signaling over β-arrestin-2 recruitment. Metadynamics
simulations of <b>5</b>’s binding to a MOR crystal structure
suggest energetically preferred binding modes that differ from crystallographic
ligands. In vivo studies with <b>5</b> demonstrate centrally
mediated antinociception, significantly reduced rewarding effects,
tolerance, and sedation. We propose that this novel MOR agonist may
represent a valuable tool in distinguishing the pathways involved
in MOR-induced analgesia from its side effects