Alkylating Derivatives of Oxotremorine Have Irreversible Actions on Muscarinic Receptors
The introduction of a β-chloroethylamino group into the structure of a drug has proven to be a successful means of developing irreversible ligands for α-adrenergic (10), muscarinic (6) and opiate receptors (2). Muscarinic agents would appear to be ideally suited for this type of chemical modification since the cationic aziridinium ring derived from a β-chloroethylmethylamino compound is structurally very similar to the trimethyl ammonium group of acetylcholine. This has been born out by the irreversible antagonist benzilylcholine mustard (6) which has proven to be a useful investigational tool in muscarinic receptor pharmacology. Recently, we and our colleagues have described some β-chloroethylamine derivatives of oxotremorine that are potent muscarinic agonists that bind irreversibly to the muscarinic receptor (3, 13, 14). The compounds, N-[4-(2-chloroethylmethylamino)-2-butynyl] -2-pyrrolidone (BM 123) and N-[4-(2-chloromethylpyrrolidino)-2-butynyl]-2-pyrrolidone (BM 130) (see Figure 1), cyclize spontaneously in neutral aqueous solutions to form aziridinium ions, which are responsible for their pharmacological effects (3, 13, 14). BM 123 and BM 130 stimulate contractions of the guinea pig ileum, and these effects are blocked by atropine, but not by hexamethonium (3, 13, 14). When injected into rats, BM 123 and BM 130 produce typical muscarinic effects including chromodacryorrhea, diarrhea, hypothermia, lacrimation, salivation and tremor. In this report, we describe some irreversible muscarinic receptor binding characteristics of BM 123 and BM 130, as well as the persistent inhibitory effect of BM 123 on acetylcholine release from the myenteric plexus of the guinea pig ileum.
KeywordsMuscarinic Receptor Longitudinal Muscle Myenteric Plexus Acetylcholine Release ALKYLATING Derivative
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