Abstract
The discovery of the natural product nodulisporic acid A (NsA A) and its potent, systemic insecticidal activity at Merck Research Laboratories in 1992 stimulated intense scientific scrutiny. Interest in this new class of indole diterpenes led to extensive delineation of its properties, both chemical and biological. Synthetic modification of NsA A served to identify its pharmacologically permissive and nonpermissive regions, produced semisynthetic derivatives with enhanced adulticidal flea efficacy (both in vitro and in vivo), and provided useful tools to support biological studies. Early observations in rodent models showed a wide therapeutic index for NsA A and detailed mechanism of action investigations demonstrated that it selectively modulated an invertebrate specific glutamate-gated ion channel for which no mammalian homolog exists. Consistent with these mechanistic conclusions, dogs treated orally with either NsA A or closely related amide analogs (15 mg / kg dosages) showed no apparent toxicity, and measurement of systemic flea efficacy in these animals demonstrated that prolonged antiparasitic activity was attained, up to 14 days subsequent to treatment with a single p.o. dose for fleas or up to 4 weeks for ticks. The extended flea efficacy was correlated to both the in vivo pharmacokinetic profile of a given analog and its intrinsic in vitro potency against fleas. In addition, studies directed towards the total synthesis of NsA A have been reported.
Keywords: nodulisporic acid, nsaa, indole diterpene, insecticidal, ivermectin
Current Topics in Medicinal Chemistry
Title: Nodulisporic Acid: Its Chemistry and Biology
Volume: 2 Issue: 7
Author(s): Peter T. Meinke, McHardy M. Smith and Wesley L. Shoop
Affiliation:
Keywords: nodulisporic acid, nsaa, indole diterpene, insecticidal, ivermectin
Abstract: The discovery of the natural product nodulisporic acid A (NsA A) and its potent, systemic insecticidal activity at Merck Research Laboratories in 1992 stimulated intense scientific scrutiny. Interest in this new class of indole diterpenes led to extensive delineation of its properties, both chemical and biological. Synthetic modification of NsA A served to identify its pharmacologically permissive and nonpermissive regions, produced semisynthetic derivatives with enhanced adulticidal flea efficacy (both in vitro and in vivo), and provided useful tools to support biological studies. Early observations in rodent models showed a wide therapeutic index for NsA A and detailed mechanism of action investigations demonstrated that it selectively modulated an invertebrate specific glutamate-gated ion channel for which no mammalian homolog exists. Consistent with these mechanistic conclusions, dogs treated orally with either NsA A or closely related amide analogs (15 mg / kg dosages) showed no apparent toxicity, and measurement of systemic flea efficacy in these animals demonstrated that prolonged antiparasitic activity was attained, up to 14 days subsequent to treatment with a single p.o. dose for fleas or up to 4 weeks for ticks. The extended flea efficacy was correlated to both the in vivo pharmacokinetic profile of a given analog and its intrinsic in vitro potency against fleas. In addition, studies directed towards the total synthesis of NsA A have been reported.
Export Options
About this article
Cite this article as:
Meinke T. Peter, Smith M. McHardy and Shoop L. Wesley, Nodulisporic Acid: Its Chemistry and Biology, Current Topics in Medicinal Chemistry 2002; 2 (7) . https://dx.doi.org/10.2174/1568026023393714
DOI https://dx.doi.org/10.2174/1568026023393714 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier
Current Pharmaceutical Design Pharmacological Intervention at Ionotropic Glutamate Receptor Complexes
Current Pharmaceutical Design Comparison of Isolation, Expansion and Cryopreservation Techniques to Produce Stem Cells from Human Exfoliated Deciduous Teeth (SHED) with Better Regenerative Potential
Current Stem Cell Research & Therapy Ligand Docking and Structure-based Virtual Screening in Drug Discovery
Current Topics in Medicinal Chemistry Green Synthesis of Silver Nanocomposites of Nigella sativa Seeds Extract for Hepatocellular Carcinoma
Current Nanomaterials Analysis of Glycosaminoglycans by Electrophoretic Approach
Current Pharmaceutical Analysis The Relaxin Peptide Family – Structure, Function and Clinical Applications
Protein & Peptide Letters Metabotropic Glutamate Receptor Genes as Candidates for Pharmacogenetic Studies of Current and Future Antipsychotic Agents in Schizophrenia
Current Pharmacogenomics Mental and Emotional Wellbeing During the COVID-19 Pandemic: The Unprecedented Malaysian Experience
Current Psychiatry Research and Reviews CAM Use in Pediatric Oncology
Current Pediatric Reviews Cutaneomeningospinal Angiomatosis (Cobb Syndrome) in a Young Patient
CNS & Neurological Disorders - Drug Targets Treating Asthma as a Neuroelectrical Disorder
Inflammation & Allergy - Drug Targets (Discontinued) Structure, Function and Control of Complement C5 and its Proteolytic Fragments
Current Molecular Medicine Hormones and the Autonomic Nervous System are Involved in Suprachiasmatic Nucleus Modulation of Glucose Homeostasis
Current Diabetes Reviews Modifiable Risk Factors Associated with Alzheimer’s Disease with Special Reference to Sleep Disturbance
CNS & Neurological Disorders - Drug Targets Docking Screens: Right for the Right Reasons?
Current Topics in Medicinal Chemistry Therapeutic Perspectives of Inhibitors of Endocannabinoid Degradation
Current Drug Targets - CNS & Neurological Disorders Dopamine D1 Receptors, Regulation of Gene Expression in the Brain, and Neurodegeneration
CNS & Neurological Disorders - Drug Targets Persistent Current Blockers of Voltage-Gated Sodium Channels: A Clinical Opportunity for Controlling Metastatic Disease
Recent Patents on Anti-Cancer Drug Discovery Can Enzyme Engineering Benefit from the Modulation of Protein Motions? Lessons Learned from NMR Relaxation Dispersion Experiments
Protein & Peptide Letters