84774-95-8Relevant academic research and scientific papers
Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists
Dewey, William L.,Gillespie, James C.,Halquist, Matthew S.,Huang, Boshi,Kulkarni, Abhishek S.,Li, Mengchu,Mendez, Rolando E.,Obeng, Samuel,Pagare, Piyusha P.,Poklis, Justin L.,Ruiz, Christian,Selley, Dana E.,Stevens, David L.,Zhang, Yan,Zheng, Yi
, (2022/03/16)
The μ opioid receptor (MOR) has been an intrinsic target to develop treatment of opioid use disorders (OUD). Herein, we report our efforts on developing centrally acting MOR antagonists by structural modifications of 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl) carboxamido] morphinan (NAP), a peripherally acting MOR-selective antagonist. An isosteric replacement concept was applied and incorporated with physiochemical property predictions in the molecular design. Three analogs, namely, 25, 26, and 31, were identified as potent MOR antagonists in vivo with significantly fewer withdrawal symptoms than naloxone observed at similar doses. Furthermore, brain and plasma drug distribution studies supported the outcomes of our design strategy on these compounds. Taken together, our isosteric replacement of pyridine with pyrrole, furan, and thiophene provided insights into the structure-activity relationships of NAP and aided the understanding of physicochemical requirements of potential CNS acting opioids. These efforts resulted in potent, centrally efficacious MOR antagonists that may be pursued as leads to treat OUD.
Rational Design, Chemical Syntheses, and Biological Evaluations of Peripherally Selective Mu Opioid Receptor Ligands as Potential Opioid Induced Constipation Treatment
Dewey, William L.,Gillespie, James C.,Huang, Boshi,Klongkumnuankarn, Pornprom,Li, Mengchu,Mendez, Rolando E.,Selley, Dana E.,Stevens, David L.,Zhang, Yan
, (2022/03/16)
Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting μ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6β-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound 19 (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.
An integrated approach toward nanobret tracers for analysis of gpcr ligand engagement
Boursier, Michelle E.,Hall, Mary P.,Hurst, Robin,Killoran, Michael P.,Kirkland, Thomas A.,Levin, Sergiy,Machleidt, Thomas,Ohana, Rachel Friedman,Zimmerman, Kristopher
supporting information, (2021/05/31)
Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a robust and sensitive method to quantify ligand engagement with specific GPCRs genetically fused to NanoLuc luciferase or the luminogenic HiBiT peptide. However, development of fluorescent tracers is often challenging and remains the principal bottleneck for this approach. One way to alleviate the burden of developing a specific tracer for each receptor is using promiscuous tracers, which is made possible by the intrinsic specificity of BRET. Here, we devised an integrated tracer discovery workflow that couples machine learning-guided in silico screening for scaffolds displaying promiscuous binding to GPCRs with a blend of synthetic strategies to rapidly generate multiple tracer candidates. Subsequently, these candidates were evaluated for binding in a NanoBRET ligand-engagement screen across a library of HiBiT-tagged GPCRs. Employing this workflow, we generated several promiscuous fluorescent tracers that can effectively engage multiple GPCRs, demonstrating the efficiency of this approach. We believe that this workflow has the potential to accelerate discovery of NanoBRET fluorescent tracers for GPCRs and other target classes.
Application of Bivalent Bioisostere Concept on Design and Discovery of Potent Opioid Receptor Modulators
Ma, Hongguang,Obeng, Samuel,Wang, Huiqun,Zheng, Yi,Li, Mengchu,Jali, Abdulmajeed M.,Stevens, David L.,Dewey, William L.,Selley, Dana E.,Zhang, Yan
, p. 11399 - 11415 (2019/12/27)
Here, we described the structural modification of previously identified μ opioid receptor (MOR) antagonist NAN, a 6α-N-7′-indolyl substituted naltrexamine derivative, and its 6β-N-2′-indolyl substituted analogue INTA by adopting the concept of "bivalent bioisostere". Three newly prepared opioid ligands, 25 (NBF), 31, and 38, were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the "address" portions of them may have negative or positive allosteric modulation effects on the function of their "message" portions compared with NAN and INTA. Collectively, our successful application of the "bivalent bioisostere concept" identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.
Structure-Activity Relationship Studies of 6α- and 6β-Indolylacetamidonaltrexamine Derivatives as Bitopic Mu Opioid Receptor Modulators and Elaboration of the message-Address Concept to Comprehend Their Functional Conversion
Obeng, Samuel,Wang, Huiqun,Jali, Abdulmajeed,Stevens, David L.,Akbarali, Hamid I.,Dewey, William L.,Selley, Dana E.,Zhang, Yan
, p. 1075 - 1090 (2018/09/18)
Structure-activity relationship (SAR) studies of numerous opioid ligands have shown that introduction of a methyl or ethyl group on the tertiary amino group at position 17 of the epoxymorphinan skeleton generally results in a mu opioid receptor (MOR) agonist while introduction of a cyclopropylmethyl group typically leads to an antagonist. Furthermore, it has been shown that introduction of heterocyclic ring systems at position 6 can favor antagonism. However, it was reported that 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(2′-indolyl)acetamido]morphinan (INTA), which bears a cyclopropylmethyl group at position 17 and an indole ring at position 6, acted as a MOR agonist. We herein report a SAR study on INTA with a series of its complementary derivatives to understand how introduction of an indole moiety with α or β linkage at position 6 of the epoxymorphinan skeleton may influence ligand function. Interestingly, one of INTA derivatives, compound 15 (NAN) was identified as a MOR antagonist both in vitro and in vivo. Molecular modeling studies revealed that INTA and NAN may interact with different domains of the MOR allosteric binding site. In addition, INTA may interact with W293 and N150 residues found in the orthosteric site to stabilize MOR activation conformation while NAN does not. These results suggest that INTA and NAN may be bitopic ligands and the type of allosteric interactions with the MOR influence their functional activity. These insights along with our enriched comprehension of the message-address concept will to benefit future ligand design.
Generation of novel radiolabeled opiates through site-selective iodination
Majumdar, Susruta,Burgman, Maxim,Haselton, Nathan,Grinnell, Steven,Ocampo, Julia,Pasternak, Anna Rose,Pasternak, Gavril W.
, p. 4001 - 4004 (2011/08/06)
Tritiated opioid radioligands have proven valuable in exploring opioid binding sites. However, tritium has many limitations. Its low specific activity and limited counting efficiency makes it difficult to examine low abundant, high affinity sites and its
SYNTHESIS OF METABOLICALLY STABLE AGENTS FOR ALCOHOL AND DRUG ABUSE
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Page/Page column 43-44, (2010/04/03)
Disclosed herein are compounds of formula (I); as defined herein, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same, and methods of using these compounds for the treatment of substance addiction.
Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessation
Ghirmai, Senait,Azar, Marc R.,Cashman, John R.
experimental part, p. 6671 - 6681 (2010/02/28)
A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (μ), delta (δ) a
Mixed k/μ opioid receptor agonists: The 6β-naltrexamines
Cami-Kobeci, Gerta,Neal, Adrian P.,Bradbury, Faye A.,Purington, Lauren C.,Aceto, Mario D.,Harris, Louis S.,Lewis, John W.,Traynor, John R.,Husbands, Stephen M.
supporting information; experimental part, p. 1546 - 1552 (2010/01/07)
Ligands from the naltrexamine series have consistently demonstrated agonist activity at κ opioid receptors (KOR), with varying activity at the μ opioid receptor (MOR). Various 6β-cinnamoylamino derivatives were made with the aim of generating ligands with
Design, synthesis, and biological evaluation of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives as μ opioid receptor selective Antagonists
Li, Guo,Aschenbach, Lindsey C.,Chen, Jianyang,Cassidy, Michael P.,Stevens, David L.,Gabra, Bichoy H.,Selley, Dana E.,Dewey, William L.,Westkaemper, Richard B.,Zhang, Yan
scheme or table, p. 1416 - 1427 (2009/12/26)
Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible μ opioid receptor (MOR) antagonist is u
