About

Palmer Taylor, Ph.D., is the Sandra and Monroe Trout Professor of Pharmacology and the Founding and Emeritus Dean of the Skaggs School of Pharmacy & Pharmaceutical Sciences at UCSD. His research employs spectroscopic physical methods, X-ray crystallography, and structural determinations to investigate principles of molecular recognition. Since the mid-1970s, he has worked with nicotinic acetylcholine receptors and acetylcholinesterase, focusing on structure and dynamics related to ligand design. His studies on acetylcholinesterase include designing reactivating antidotes for organophosphate nerve agent and insecticide exposure, aiming for oral bioavailability and CNS reactivation capabilities. These efforts involve collaboration with Barry Sharpless of TSRI, utilizing click chemistry to synthesize selective cholinesterase inhibitors and reactivator antidotes. Taylor's work also extends to the structure and function of neuroligin and neurexin, proteins involved in post-synaptic adhesion, employing crystallographic and solution-based techniques to understand macromolecular recognition of ectodomain adhesion molecules.

Research topics

• Chemistry
• Stereochemistry
• Biochemistry
• Biology
• Biophysics

Selected publications

• The ionizing zwitterionic oxime antidote attenuates gliosis in mice exposed to sarin

  Chemico-Biological Interactions · 2025-09-30

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• 4 Information Access and Resilience for Newcomer Groups: Yazidi and Turkish- Speaking Newcomers in York Region

  McGill-Queen's University Press eBooks · 2025-10-15

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• Click-chemistry-derived oxime library reveals efficient reactivators of nerve agent-inhibited butyrylcholinesterase suitable for pseudo-catalytic bioscavenging

  Archives of Toxicology · 2025-03-03 · 8 citations

  articleOpen access

  Abstract A library of 100 click-chemistry-derived oximes was evaluated as reactivators of butyrylcholinesterase (BChE) inhibited by the nerve agents (NAs) sarin, cyclosarin, VX, and tabun. While reactivation efficiency was highly dependent on the structure of both the NA and the oxime, for each NA-BChE conjugate, we identified reactivators more effective than currently approved oximes for NA poisoning. Detailed kinetic analysis indicated that this enhancement results from both improved molecular recognition—specifically, enhanced binding affinity of the phosphylated conjugates for the oximes—and increased maximal reactivation rates. Molecular modeling of oximes in a near-attack conformation within inhibited BChE revealed critical interactions for productive reactivation. Among all tested oximes, 5B [1-hexyl-2-((hydroxyimino)methyl)pyridinium chloride] emerged as a particularly efficient reactivator for BChE phosphorylated with cyclosarin, with the highest observed overall reactivation rate of 34,120 M −1 min −1 , which is 525-fold and 44-fold higher than the reference oximes 2-PAM and HI-6, respectively. In general, three mono-pyridinium mono-oximes demonstrated more efficient recovery of BChE activity than bis-pyridinium triazole-annulated click-chemistry bis-oximes, which were previously identified as potent reactivators for inhibited acetylcholinesterase (AChE). Ex vivo assessment of reactivation potency demonstrated that the combined addition of BChE with one efficient reactivator for BChE and another for AChE achieved > 90% reactivation of cyclosarin-inhibited cholinesterases in whole blood (WB), demonstrating near-complete degradation of a 100-fold excess of cyclosarin within 6 min. These results confirm that oxime-assisted catalysis is feasible for NA bioscavenging in blood and underscore BChE’s potential as a target for developing therapies against NA poisoning.

  PublisherOA PDFDOI

• RS194B oxime mediated AChE-reactivation and protection in lethal sarin and insecticide organophosphate exposed macaques is accompanied by oxime-independent BChE increases; likely a result of liver damage

  Chemico-Biological Interactions · 2025-05-24 · 2 citations

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• The Cyclic Imine Core Common to the Marine Macrocyclic Toxins Is Sufficient to Dictate Nicotinic Acetylcholine Receptor Antagonism

  Marine Drugs · 2024-03-27 · 1 citations

  articleOpen access

  Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.

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• Transport Inhibitors to enhance central and peripheral nervous system antidote activity to organophosphate (OP) exposure

  Journal of Pharmacology and Experimental Therapeutics · 2024-05-13 · 1 citations

  articleSenior author
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• A single post‐exposure oxime <scp>RS194B</scp> treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides

  Journal of Neurochemistry · 2023-02-14 · 7 citations

  articleOpen accessSenior authorCorresponding

  Millions of individuals globally suffer from inadvertent, occupational or self-harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP-inhibited AChE. However, animal model studies and recent clinical trials using insecticide-poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood-brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP-inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post-exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1-2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non-invasive treatment, especially in isolated rural settings.

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• Social trust among refugees: Using a human rights lens to understand refugee experiences.

  American Psychological Association eBooks · 2022-01-01 · 1 citations

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• Differential Activation and Desensitization States Promoted by Noncanonical α 7 Nicotinic Acetylcholine Receptor Agonists

  Journal of Pharmacology and Experimental Therapeutics · 2022-09-02 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

• Interactions of Nereistoxin and Its Analogs with Vertebrate Nicotinic Acetylcholine Receptors and Molluscan ACh Binding Proteins

  Marine Drugs · 2022-01-04 · 12 citations

  articleOpen accessSenior author

  Nereistoxin (NTX) is a marine toxin isolated from an annelid worm that lives along the coasts of Japan. Its insecticidal properties were discovered decades ago and this stimulated the development of a variety of insecticides such as Cartap that are readily transformed into NTX. One unusual feature of NTX is that it is a small cyclic molecule that contains a disulfide bond. In spite of its size, it acts as an antagonist at insect and mammalian nicotinic acetylcholine receptors (nAChRs). The functional importance of the disulfide bond was assessed by determining the effects of inserting a methylene group between the two sulfur atoms, creating dimethylaminodithiane (DMA-DT). We also assessed the effect of methylating the NTX and DMA-DT dimethylamino groups on binding to three vertebrate nAChRs. Radioligand receptor binding experiments were carried out using washed membranes from rat brain and fish (Torpedo) electric organ; [3H]-cytisine displacement was used to assess binding to the predominantly high affinity alpha4beta2 nAChRs and [125I]-alpha-bungarotoxin displacement was used to measure binding of NTX and analogs to the alpha7 and skeletal muscle type nAChRs. While the two quaternary nitrogen analogs, relative to their respective tertiary amines, displayed lower α4β2 nAChR binding affinities, both displayed much higher affinities for the Torpedo muscle nAChR and rat alpha7 brain receptors than their respective tertiary amine forms. The binding affinities of DMA-DT for the three nAChRs were lower than those of NTX and MeNTX. An AChBP mutant lacking the C loop disulfide bond that would potentially react with the NTX disulfide bond displayed an NTX affinity very similar to the parent AChBP. Inhibition of [3H]-epibatidine binding to the AChBPs was not affected by exposure to NTX or MeNTX for up to 24 hr prior to addition of the radioligand. Thus, the disulfide bond of NTX is not required to react with the vicinal disulfide in the AChBP C loop for inhibition of [3H]-epibatidine binding. However, a reversible disulfide interchange reaction of NTX with nAChRs might still occur, especially under reducing conditions. Labeled MeNTX, because it can be readily prepared with high specific radioactivity and possesses relatively high affinity for the nAChR-rich Torpedo nAChR, would be a useful probe to detect and identify any nereistoxin adducts.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21NS072086

  NIH · $907k · 2013

• NIH Grant R01GM018360

  NIH · $6.9M · 2014

• NIH Grant R37GM018360

  NIH · $6.3M · 2009

• NIH Grant P01HL035018

  NIH · $17.4M · 2009

• NIH Grant U01NS058046

  NIH · $4.0M · 2012

Frequent coauthors

• Zoran Radić

  342 shared

• Todd T. Talley

  University of California, San Diego

  123 shared

• K. Barry Sharpless

  Scripps Research Institute

  107 shared

• Zrinka Kovarik

  University of Zagreb

  100 shared

• Valery V. Fokin

  University of Southern California

  90 shared

• P. Marchot

  Aix-Marseille Université

  85 shared

• Davide Comoletti

  Rutgers, The State University of New Jersey

  84 shared

• Kwok‐Yiu Ho

  University of Montana

  80 shared

Education

• BS., Ph.D., Pharmacy

  University of Wisconsin Madison

  1965

Awards & honors

• Fogarty Fellow, Darwin College, Cambridge University (1981-8…
• President, American Society for Pharmacology & Experimental…
• Honorary Membership, American Society for Clinical Investiga…
• Elected to the National Academy of Medicine (1998)
• NIGMS Merit Award (1999-2009)