Tertiary 3- and 4-haloalkylamine analogues of oxotremorine as prodrugs of potent muscarinic agonists.
A series of tertiary 3- and 4-haloalkylamines related to the muscarinic agent oxotremorine was synthesized. The compounds cyclized in neutral aqueous solution to quaternary ammonium salts, which, in contrast to the parent haloalkylamines, were potent muscarinic agonists in vitro. When administered systemically to mice, the haloalkylamines produced central (tremor and analgesia) and peripheral (salivation) muscarinic effects. Central potency was dependent on the rate of cyclization and on the route of administration. The N-methyl-N-(4-chlorobutyl)amine derivative 7 cyclized rapidly (t1/2 less than 0.4 min at 37 degrees C) and elicited tremor on iv but not on ip injection, whereas the N-methyl-N-(3-chloropropyl)amine 3 cyclized slowly (t1/2 = 436 min) and was not tremorogenic by either route of administration. The N-methyl-N-(3-bromopropyl)amine 4(t1/2 = 11 min) and its iodo analogue 5 (t1/2 = 14 min) were quite potent in eliciting central muscarinic effects on both iv and ip injection to mice. It is concluded that haloalkylamine analogues of oxotremorine may serve in vivo as prodrugs for potent quaternary ammonium salts and that they are capable of circumventing the blood-brain barrier to such salts.
Ringdahl
B
B
Department of Pharmacology, School of Medicine, University of California, Los Angeles 90024-1735.
Roch
M
M
Jenden
D J
DJ
D000698:Analgesia; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010095:Oxotremorine / Q000031:analogs & derivatives*; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*; D011355:Prodrugs / Q000138:chemical synthesis*; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D012463:Saliva / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014202:Tremor / Q000503:physiopathology
D007202:Indicators and Reagents; D010277:Parasympathomimetics; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D011760:Pyrrolidinones; D010095:Oxotremorine