Doctor of Philosophy
James F. Stubbins
Poisoning by organophosphate cholinesterase inhibitors results in a rapid rise in acetylcholine (ACh) in the synapse and many pronounced pharmacological effects in numerous tissues in the body. The treatment for organophosphorus poisoning involves administration of a cholinesterase—reactivating oxime to restore the activity of the cholinesterase and an antimuscarinic agent to block the response to the excess ACh. Presently atropine is the standard antimuscarinic agent used clinically as an antidote. This research was directed toward finding an antimuscarinic agent better than atropine as an antidote.
Since caramiphen and aprophen have been reported to be effective antidotes we synthesized numerous structural variations of these molecules with the aim of enhancing the antimuscarinic and antidotal properties. Many of these compounds showed enhanced antimuscarinic properties. We synthesized analogs of caramiphen which have different substituents in the para position of the phenyl ring. The purpose of the set was to test the effect of different substituents on the antimuscarinic and antidotal activity and to look for any possible relationship of activity with substituent parameters such as Hammett’s sigma (σ) or Hansch’s pi (π) values. Four substituents were selected which have extreme values for sigma and pi in a positive or negative direction, in all combinations. The substituents chosen for use in this approach were the amino (-σ, -π); 1-‘ tetrazolyl (+σ, -π); l-pyrrolidinyl (-σ, +π); and the trifluoromethyl (+σ, +π).
Some N-substituted-1,6-hexanediamines were synthesized to examine the SAR for antimuscarinic and antidotal properties of this series. In a binding assay these compounds showed moderate affinity with a preference for the M2 receptor subtype. It was determined the bis-quaternary structure was not mandatory for muscarinic activity. The optimum compound of this series was N,N’-dimethyl-N,N’-bis[3-(2- phthalimido)propyl]-1,6-hexanediamine.
Also, a number of literature and currently manufactured antimuscarinics were obtained. All of the compounds are being screened in a number of in vitro and in vivo assays designed to give information on the SAR for the pharmacological properties which might be important as an antidote.
Current information from this research indicates the best antidotes are not the best antimuscarinics in the pharmacological assays. Good central antimuscarinic activity is the primary property of a good antidote, although the antidotal effectiveness of an agent can not be described solely based on its antimuscarinic properties.
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