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ToxSci Advance Access published online on August 27, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg216
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received June 11, 2003; accepted August 7, 2003
© 2003 Society of Toxicology

Neurotoxicology

Toxicological and Structural Features of Organophosphorus and Organosulfur Cannabinoid CB1 Receptor Ligands

Yoffi Segall 1, Gary B. Quistad 1, Susan E. Sparks 1, Daniel K. Nomura 1, and John E. Casida 1*

1 Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112

* To whom correspondence should be addressed. E-mail: ectl{at}nature.berkeley.edu.


  Abstract

Potent cannabinoid CB1 receptor ligands include anandamide [N-(2-hydroxyethyl)arachidonamide], {Delta}9-tetrahydrocannabinol and [3H]CP 55,940 at the agonist site and selected organophosphorus esters (including some pesticides) and organosulfur compounds at a proposed closely-coupled "nucleophilic" site. This study considers the toxicological and structural features of alkylfluorophosphonates, benzodioxaphosphorin oxides, alkanesulfonyl fluorides and analogs acting at the nucleophilic site. Binding at the agonist site, using [3H]CP 55,940 in assays with mouse brain membranes, is inhibited by O-isopropyl dodecylfluorophosphonate (compound 2), dodecanesulfonyl fluoride (compound 14) and dodecylbenzodioxaphosphorin oxide with IC50 values of 2-11 nM. Compounds 2 and 14 are also effective in vivo, with 84% inhibition of mouse brain CB1 binding 4 h after intraperitoneal dosage at 30 mg/kg. Compound 14-inhibited CB1 in mouse brain requires about 3-4 days for recovery of 50% activity, suggesting covalent derivatization. Delayed toxicity (mortality in 0.3-5 days) from compounds 2, 14 and octanesulfonyl fluoride (18) is more closely associated with in vivo inhibition of brain neuropathy target esterase - lysophospholipase (NTE-LysoPLA) than with that of CB1 or acetylcholinesterase. NTE-LysoPLA inhibited by sulfonyl fluorides 14 and 18 cannot "age," a proposed requirement for NTE phosphorylated by organophosphorus delayed neurotoxicants. Several octane- and dodecanesulfonamides with N-(2-hydroxyethyl) and other substituents based on anandamide give depressed mobility and recumbent posture in mice, but the effects do not correlate with potency for CB1 inhibition in vitro. Specific toxicological responses are not clearly associated with organophosphorus- or organosulfur-induced inhibition of the proposed CB1 nucleophilic site in mouse brain. On the other hand, the most potent CB1 inhibitors examined here are also NTE-LysoPLA inhibitors and cause delayed toxicity in mice.

Key Words: cannabinoid receptor, CB1, dodecanesulfonyl fluoride, O-isopropyl dodecylfluorophosphonate, neuropathy target esterase, lysophospholipase, fatty acid amide hydrolase .


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