Alkylating derivative of oxotremorine interacts irreversibly with the muscarinic receptor

Journal Article · Mon Mar 05 00:00:00 EST 1984 · Life Sci.; (United States)

DOI:https://doi.org/10.1016/0024-3205(84)90303-5· OSTI ID:6304637

Ehlert, F J; Jenden, D J; Ringdahl, B

A 2-chloroethylamine derivative of oxotremorine was studied in pharmacological experiments and muscarinic receptor binding assays. The compound, N-(4-(2-chloroethylmethylamino)-2-butynyl)-2-pyrrolidone (BM 123), forms an aziridinium ion in aqueous solution at neutral pH that stimulates contractions of guinea pig ileum with a potency similar to that of oxotremorine. Following the initial stimulation, there is a long lasting period of lack of sensitivity of the guinea pig ileum to muscarinic agonists. BM 123 also produces muscarinic effects in vivo. When homogenates of the rat cerebral cortex were incubated with BM 123 and assayed subsequently in muscarinic receptor binding assays, a loss of binding capacity for the muscarinic antagonist, (/sup 3/H)N-methylscopolamine ((/sup 3/H)NMS), was noted without a change in affinity. Similar observations were made in (/sup 3/H)1-3-quinuclidinyl benzilate ((/sup 3/H)-QNB) binding assays on the forebrains of mice that had been injected with BM 123 24 hr earlier. The loss in receptor capacity for both (/sup 3/H)NMS and (/sup 3/H)-QNB was prevented by atropine treatment. Kinetic studies of the interaction of BM 123 with homogenates of the rat cerebral cortex in vitro showed that the half-time for the loss of (/sup 3/H)-QNB binding sites increased from 10 to 45 min as the concentration of BM 123 decreased from 10 to 1 ..mu..M. In contrast to the aziridinium ion, the parent 2-chloroethylamine compound and the alcoholic hydrolysis product were largely devoid of pharmacological and binding activity.

• Research Organization: Univ. of California, Los Angeles
• OSTI ID: 6304637
• Journal Information: Life Sci.; (United States), Vol. 34:10
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
PYRROLIDONES
BIOCHEMICAL REACTION KINETICS
RADIOASSAY
RECEPTORS
AFFINITY
BRAIN
CEREBRAL CORTEX
CONTRACTION
GUINEA PIGS
LABELLED COMPOUNDS
MICE
RATS
SMALL INTESTINE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMIDES
ANIMALS
AZOLES
BODY
CENTRAL NERVOUS SYSTEM
CEREBRUM
DIGESTIVE SYSTEM
GASTROINTESTINAL TRACT
HETEROCYCLIC COMPOUNDS
INTESTINES
ISOTOPE APPLICATIONS
KINETICS
LACTAMS
MAMMALS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PYRROLES
REACTION KINETICS
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques