ArticleThe AAPS journal2010
Identification of two novel, potent, low-liability antinociceptive compounds from the direct in vivo screening of a large mixture-based combinatorial library.
Article in The AAPS journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed.
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- Synthesis of Diazacyclic and Triazacyclic Small-Molecule Libraries Using Vicinal Chiral Diamines Generated from Modified Short Peptides and Their Application for Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Article
- Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide.Molecules (Basel, Switzerland) · 2023Article
- Polyheterocyclic peptidomimetics: Parallel solid phase synthesis of oligo cyclic guanidines and their inhibition activity against Mycobacterium tuberculosis DNA gyrase.Bioorganic & medicinal chemistry letters · 2023Article
- Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics.International journal of molecular sciences · 2022Article
- Glioblastoma Extracellular Vesicle-Specific Peptides Inhibit EV-Induced Neuronal Cytotoxicity.International journal of molecular sciences · 2022Article
- Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain.Molecules (Basel, Switzerland) · 2022Article
- Expression of Human Immunodeficiency Virus Transactivator of Transcription (HIV-TatJournal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2022Article
- An analog of [d-Trp]CJ-15,208 exhibits kappa opioid receptor antagonism following oral administration and prevents stress-induced reinstatement of extinguished morphine conditioned place preference.Pharmacology, biochemistry, and behavior · 2022Article
- 1,5-Disubstituted Acylated 2-Amino-4,5-dihydroimidazoles as a New Class of Retinoic Acid Receptor-Related Orphan Receptor (ROR) Inhibitors.International journal of molecular sciences · 2022Article
- Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology.Pharmacology & therapeutics · 2022Review
- Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use.International journal of molecular sciences · 2022Article
- Malaria Parasite Plasmodium falciparum Proteins on the Surface of Infected Erythrocytes as Targets for Novel Drug Discovery.Biochemistry. Biokhimiia · 2022Review
- Peptide Kappa Opioid Receptor Ligands and Their Potential for Drug Development.Handbook of experimental pharmacology · 2022Review
- Oxidative Metabolism as a Modulator of Kratom's Biological Actions.Journal of medicinal chemistry · 2021Article
- Development of New Benzylpiperazine Derivatives as σACS chemical neuroscience · 2021Article
- Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.Journal of medicinal chemistry · 2021Article
- Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site.eLife · 2021Article
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Authors and funding
6 authors.
Funding
Abstract
Synthetic combinatorial methods now make it practical to readily produce hundreds of thousands of individual compounds, but it is clearly impractical to screen each separately in vivo. We theorized that the direct in vivo testing of mixture-based combinatorial libraries during the discovery phase would enable the identification of novel individual compounds with desirable antinociceptive profiles while simultaneously eliminating many compounds with poor absorption, distribution, metabolism, or pharmacokinetic properties. The TPI 1346 small-molecule combinatorial library is grouped in 120 mixtures derived from 26 functionalities at the first three positions and 42 functionalities at the fourth position of a pyrrolidine bis-cyclic guanidine core scaffold, totaling 738,192 compounds. These 120 mixtures were screened in vivo using the mouse 55 degrees C warm water tail-withdrawal assay to identify mixtures producing antinociception. From these data, two fully defined individual compounds (TPI 1818-101 and TPI 1818-109) were synthesized. These were examined for antinociceptive, respiratory, locomotor, and conditioned place preference effects. The tail-withdrawal assay consistently demonstrated distinctly active mixtures with analgesic activity that was blocked by pretreatment with the non-selective opioid antagonist, naloxone. Based on these results, synthesis and testing of TPI 1818-101 and 1818-109 demonstrated a dose-dependent antinociceptive effect three to five times greater than morphine that was antagonized by mu- or mu- and kappa-opioid receptor selective antagonists, respectively. Neither 1818-101 nor 1818-109 produced significant respiratory depression, hyperlocomotion, or conditioned place preference. Large, highly diverse mixture-based libraries can be screened directly in vivo to identify individual compounds, potentially accelerating the development of promising therapeutics.
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