Disease relevance of 1-[4-(2-chloroethyl-methyl-amino)but-2-ynyl]pyrrolidin-2-one

• Recovery from BM 123 alkylation occurred in NG108-15 neuroblastoma X glioma cells [1].

High impact information on 1-[4-(2-chloroethyl-methyl-amino)but-2-ynyl]pyrrolidin-2-one

• The kinetics of the alkylation of muscarinic receptors by BM 123 were consistent with a model in which the aziridinium ion rapidly forms reversible complexes with superhigh high and low affinity sites which slowly convert to covalent complexes [2].
• Incubation of the isolated guinea pig ileum for 30 min with BM 123 at 20 microM and 2 microM caused 94% and 48% receptor alkylation, respectively, as calculated from the shift in the agonist dose-response curve [3].
• BM 130 was a weak agonist at nicotinic receptors of the frog rectus abdominis muscle, whereas BM 123 was almost inactive [3].
• The role of muscarinic receptors in the regulation of (3H)-acetylcholine (3H-Ach) release from the hippocampus was investigated with the irreversible cholinergic agonist BM-123 (N-[4(2-chloroethylmethylamino)-2-butynyl]2-pyrrolidone) [4].
• Muscarinic receptors from rat cerebral cortex were found to recover from alkylation by the specific ligand N-[-(2-chloroethyl-methylamino)-2-butynyl]-2-pyrrolidone (BM 123) without the benefit of cellular integrity, i.e., in washed membranes incubated at 37 degrees C for relatively long times (days) [5].

Biological context of 1-[4-(2-chloroethyl-methyl-amino)but-2-ynyl]pyrrolidin-2-one

• It was possible to alkylate the high and low affinity sites selectively with BM 123 by taking advantage of kinetic differences in the rates of alkylation of these two sites [2].
• Thus, central potency of 2-haloethylamines such as BR 401 and BM 123 is critically dependent not only on the rate of cyclization, but also on the route of administration [6].
• The reversible binding characteristics of both BM 123 and BM 123A were investigated in competitive binding experiments with N-[3H]methylscopolamine at 0 degree C, conditions under which little or no receptor alkylation occurs [7].
• Upon i.v. administration, BR 401 was 2- to 3-fold more potent than oxotremorine and 10 to 20 times more potent than BM 123 in producing central (tremor and analgesia) and peripheral (salivation) muscarinic effects [6].
• 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 [3H]1-QNB binding sites increased from 10 to 45 min as the concentration of BM 123 decreased from 10 to 1 microM [8].

Anatomical context of 1-[4-(2-chloroethyl-methyl-amino)but-2-ynyl]pyrrolidin-2-one

• BM 123, because of its slower cyclization, enters the central nervous system effectively also by the i.p. route [6].
• Similar observations were made in [3H]1-3-quinuclidinyl benzilate ( [3H]1-QNB) binding assays on the forebrains of mice that had been injected with BM 123 24 hr earlier [8].

Analytical, diagnostic and therapeutic context of 1-[4-(2-chloroethyl-methyl-amino)but-2-ynyl]pyrrolidin-2-one

• Spontaneous regeneration of free muscarinic receptor after alkylation by BM 123. I. Recovery in vivo and in cell culture [1].

References