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D J Jenden

Publications and source records attributed to D J Jenden.

At least 55 records · Page 3Linked to original sources
PubMed1990

Tertiary 2-haloethylamine derivatives of the muscarinic agent McN-A-343, [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride.

4-[(2-Chloroethyl)methylamino]-2-butynyl N-(3-chlorophenyl)carbamate (2) and 4-[(2-bromoethyl)methylamino]-2-butynyl N-(3-chlorophenyl)carbamate (3) were synthesized. Compounds 2 and 3 cyclized at neutral pH to an aziridinium ion (4). The rate constants for the cyclization of 2 and 3 at 37 degrees C were about 0.01 and 0.4 min-1, respectively, as measured by titrimetric analysis and by 1H NMR spectroscopy. The aziridinium ion had 1/4 the potency of McN-A-343 (1) as a ganglionic muscarinic stimulant in the anesthetized, pentolinium-treated rat but showed no muscarinic effects on the isolated guinea pig ileum. It caused alkylation of muscarinic receptors in homogenates of the rat cerebral cortex. An irreversible blockade of central muscarinic receptors was also observed after intravenous administration of 3 to mice. Because of its selectivity, irreversible actions, and ability to pass into the central nervous system, 3 should become a valuable tool in studies of muscarinic receptors.

Alkylation↗
PubMed1989

Effects of chronic in vivo replacement of choline with a false cholinergic precursor.

Chronic administration to rats of a diet in which all choline is replaced by NADe, an unnatural choline analog, results in a classical hypocholinergic syndrome characterized by progressive loss of learning and memory, hyperkinesis, hyperreactivity and hyperalgesia. Discontinuation of the artificial diet results in rapid elimination of NADe from both free and phospholipid-bound pools in all tissues studied, but the behavioral effects recede more slowly and incompletely. These results are consistent with a model in which choline and NADe compete in both acetylcholine and phospholipid synthesis, resulting in selective vulnerability of cholinergic neurons. Histological studies are in progress to determine whether microanatomical changes are also consistent with this model.

Animals↗
PubMed1989

Factors influencing erythrocyte choline concentrations.

Choline concentrations in human erythrocytes increase after freezing and thawing, during incubation in Krebs-phosphate for 30 min or on storage at 0 degrees C for 3-24 hr. The increase is prevented by protein precipitation by 10% perchloric acid, 10% zinc hydroxide, 10% sodium tungstate or boiling in water. It is not prevented by EDTA (10 mM) and is increased by oleate (5 mM). We suggest that the increase is due to the action of phospholipase D on erythrocyte phospholipids.

Calcium↗
PubMed1989

Roles of neurotransmitter receptors in behavior: recovery of function following decreases in muscarinic receptor density induced by cholinesterase inhibition.

Cholinergic neurotransmitter levels were elevated in rat brain by reducing its inactivating enzyme, acetylcholinesterase (AChE), with an anti-AChE agent. Elevated levels result in decreases in cholinergic (muscarinic) receptors. Withdrawal of agent after 10 days of chronic treatment began a gradual return of neurochemical variables toward normal states, yet not fully achieving them within the following 29 days of the experiment. All behavioral and physiological variables measured showed significant effects at the start of the treatment period, developing tolerance at different rates as treatments continued. They also recovered differentially during withdrawal. Results are consistent with a theoretical model in which thresholds for normal functioning of different behavioral and physiological processes are associated with different receptor densities.

Acetylcholine↗
PubMed1989

Focal ischemia enhances choline output and decreases acetylcholine output from rat cerebral cortex.

Choline concentration is rate limiting in the synthesis of acetylcholine. There is a negative arteriovenous difference for choline concentration across the brain, indicating the steady output of choline from this organ. Cerebral ischemia may increase extracellular choline concentration by interfering with its removal by the circulation and by enhancing its net production from phospholipids. We tested this hypothesis in six rats subjected to middle cerebral artery occlusion. We determined choline and acetylcholine output from the ischemic cerebral cortex by analyzing their concentrations in the fluid contained in cortical cups by gas chromatography-mass spectrometry. Mean +/- SEM choline output over 40 minutes before ischemia (baseline value) was 31.1 +/- 1.6 pmol/min/cm2. During ischemia, mean +/- SEM choline output rose to 100.8 +/- 13, 97.3 +/- 12.7, 100 +/- 22.4, and 93.1 +/- 16.9 pmol/min/cm2 in four consecutive 10-minute periods, respectively. Mean +/- SEM acetylcholine output was 15.6 +/- 1.1 before and 5.9 +/- 1.2, 8.3 +/- 2.6, 8.6 +/- 2.1, and 13.7 +/- 4.6 pmol/min/cm2 in the four 10-minute collection periods during ischemia. All four choline values and the first acetylcholine value during ischemia were significantly different from their respective baseline values. We conclude that ischemia induces an increase in extracellular choline concentration with possible implications for acetylcholine metabolism. The attending transient decline in acetylcholine output may be due to impaired release due to local hypoxia or to decreased acetylcholine synthesis.

Acetylcholine↗
PubMed1989

Effects of middle cerebral artery occlusion on cerebral cortex choline and acetylcholine in rats.

We measured regional cerebral blood flow and acetylcholine and choline concentrations in tissue fragments of normally perfused and ischemic cortical regions from 10 rats. Tissue uptake of [14C]iodoantipyrine was used to indicate regional cerebral blood flow, and gas chromatography-mass spectrometry was used to measure acetylcholine and choline concentrations. Cerebral cortical ischemia was induced by permanent occlusion of the middle cerebral artery, and variables were measured 2.5 or 24 hours later. A close correlation was found between tissue choline concentration and the reciprocal of regional cerebral blood flow. A large increase in tissue choline concentration was observed in the ischemic cortex. Choline production rate was estimated by plotting choline concentration against the reciprocal of regional cerebral blood flow. This rate was independent of choline concentration. Acetylcholine concentration, on the other hand, was constant in ischemic and normally perfused regions, except in the center of the ischemic region 2.5 hours after middle cerebral artery occlusion, where a significant decrease was observed.

Acetylcholine↗
PubMed1989

Muscarinic actions and receptor binding of the enantiomers of BM 130, an alkylating analog of oxotremorine.

The enantiomers of the oxotremorine analog N-[4-(2-chloromethylpyrrolidine)-2-butynyl]-2-pyrrolidone (BM 130) were synthesized. The LD50 values of (+)- and (-)-BM 130 in mice (i.v.) were 10.4 +/- 1.4 and 13.5 +/- 1.9 mumol/kg, respectively. Atropine and N-methylatropine poorly protected against the lethal effects, suggesting that they were nonmuscarinic in nature. When administered i.v. to mice, (+)- and (-)-BM 130 were equipotent in producing peripheral and central muscarinic effects. ED50 values were 1.3 to 1.4, 2.8 to 3.2 and 0.20 to 0.26 mumol/kg, respectively, for salivation, tremor and analgesia (tail-flick assay). After i.p. injection, tremor was not observed and analgesic potency was reduced more than 10-fold compared to the i.v. route. The aziridinium ions [(+)- and (-)-BM 130A], formed by spontaneous cyclization of (+)- and (-)-BM 130, were virtually equipotent in eliciting contractions of the isolated guinea pig ileum and in causing salivation in mice. Their LD50 values in mice (i.v.) were 1.1 +/- 0.2 and 2.1 +/- 0.3 mumol/kg, respectively. The enantiomers of BM 130A had similar affinity for muscarinic receptors in the rat cerebral cortex as measured by competitive inhibition of (-)-[3H]N-methylscopolamine binding at 0 degrees C. The rate constants for alkylation of muscarinic receptors, obtained at 37 degrees C by measuring the decline in (-)-[3H]-3-quinuclidinyl benzilate binding to cortical homogenates that had been treated with various concentrations of (+)- and (-)-BM 130A for 20, 45 or 90 min, differed significantly for the two enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗
PubMed1989

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

The recovery of rat muscarinic receptor number from the effects of a specific alkylating ligand, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123), in three tissues is presented as an exponential function of time. No significant difference was found in the recovery rate constants derived from analysis of recovery time courses in corpus striatum, cerebral cortex and ileal longitudinal muscle. The single rate constant (0.021/hr) was also independent of amount and duration of BM 123 dose. Additional analysis of agonist-defined high and low affinity subsites in cortex revealed that recovery of these populations also followed similar time courses although the alkylation proceeds more slowly for the high affinity sites. The rate constant for recovery of both subsites was 0.029/hr. Recovery from BM 123 alkylation occurred in NG108-15 neuroblastoma X glioma cells. The presence of cycloheximide in the recovery medium did not significantly inhibit this recovery process in the clonal cell line, suggesting that de novo receptor synthesis is unnecessary for regeneration of unalkylated receptors.

Alkylation↗
PubMed1989

Spontaneous regeneration of free muscarinic receptor after alkylation by BM 123. II. Recovery in broken cell preparations.

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). Unalkylated receptor number increased in alkylated preparations whether viewed as femtomoles per milligram of protein or as a percentage of the atropine-protected control. The rate of recovery was independent of pH over the range 6 to 9 and it was slowed but not eliminated by incubation at 4 degrees C. Muscarinic receptor recovery from BM 123 was linearly dependent on the concentration of alkylated receptors, indicating first-order kinetics and yielding a rate constant 0.026/hr. Of the other chloroethylamines examined for evidence of in vitro muscarinic receptor recovery from alkylation, only one, phenoxybenzamine, exhibited irreversible receptor blockade under these conditions. Each of the others showed different rates for regeneration of free receptors.

Alkylation↗
PubMed1988

Persisting behavioral and neurochemical deficits in rats following lesions of the basal forebrain.

The effects of excitotoxic lesions of the nucleus basalis magnocellularis on cortical cholinergic activity and passive avoidance performance were examined in rats at 6, 14, 84 and 180 days after lesioning. Lesioned rats showed significant impairment of passive avoidance retention at every time point tested, with no evidence of behavioral recovery compared to unoperated and sham-lesioned (i.e., vehicle-injected) control rats. Cortical choline acetyltransferase (CAT) activity was reduced relative to controls at all time points examined, with the greatest reduction (i.e., 28%) occurring at approximately 14 days after lesioning. The levels of CAT activity at 180 postlesioning remained reduced compared to control animal levels, but less so than at 14 days after lesioning, indicating partial recovery. No changes in cholinergic muscarinic binding were observed at any time following lesioning. The results indicate that the behavioral and neurochemical effects of NbM lesions persist for at least 6 months following lesioning, but that partial, gradual recovery of cholinergic activity occurs.

Animals↗
PubMed1988

Effects of an irreversible muscarinic agonist (BM123) on avoidance and spontaneous alternation performance.

The present study sought to assess whether the compound N-[4-(2-chloro-ethylmethylamine)-2-butynyl]-2-pyrrolidone (BM123), a potent muscarinic agonist that binds irreversibly to the muscarinic receptor (mAChR), has long-lasting functional effects which may be related to a reduction in functional mAChRs. Passive (inhibitory) avoidance performance, one-way active avoidance learning, and spontaneous alternation behavior were studied in rats. The results confirmed the acute muscarinic stimulating effects of BM123, including tremor, salivation, chromodacryorrhea and hypothermia. In addition, when measured 3-4 days after administration, rats treated with BM123 had disrupted spontaneous alternation performance and tended to have impaired performance for the inhibitory avoidance task with facilitated acquisition of active avoidance. This spectrum of effects is consistent with previous reports showing a 20-40% reduction in mAChRs at these times after BM123. The reversible muscarinic agonist, oxotremorine, was without significant effect. In a further experiment, it was found that pretreatment with methyl atropine did not prevent the disruption of spontaneous alternation behavior by BM123, whereas pretreatment with atropine did. Thus, these long-lasting behavioral effects of BM123 are related to its alkylation of and subsequent reduction in central mAChRs.

Animals↗
PubMed1988

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.

Analgesia↗
PubMed1988

A device to evoke acetylcholine release electrically in the guinea pig myenteric plexus/longitudinal muscle preparation through mass electrodes.

A stimulator was developed to evoke acetylcholine release in the myenteric plexus-longitudinal muscle preparation from the guinea pig ileum. A power output stage was devised to allow a conventional stimulator to drive the low impedance presented by this type of preparation. To eliminate electrode polarization, the polarity of the stimulus is alternated. A peak reading ammeter is included which allows the investigator to monitor the stimulus.

Acetylcholine↗
PubMed1987

Influence of atropine and N-methyl atropine pretreatments on behavioral and physiological effects of the irreversible muscarinic agonist, BM123.

The irreversible muscarinic agonist, BM123 (63 mu moles kg-1, IV), was shown to produce central and peripheral physiological signs characteristic of cholinergic agonists. It also induced hypothermia, elevated nociceptive thresholds, reduced locomotor activity and disrupted spontaneous alternation performance in rats. The centrally acting muscarinic antagonist, atropine (50 mu mole kg-1) prevented or reduced all the above effects of BM123 when given SC 40 min prior to the BM123 injection. In contrast, the peripherally acting muscarinic antagonist, N-methyl atropine, prevented only the peripheral effects and the elevated nociceptive thresholds. Habituation of activity during a 20 min session was observed in all groups despite different levels of general activity. These findings are consistent with a model in which atropine and N-methyl atropine compete with BM123 for reversible association with the muscarinic receptor. In the case of BM123 administered alone, the association results, first, in agonist effects and proceeds to form an irreversible complex. Our present results show that by competing with BM123 for mAChR sites during the initial, reversible state of the interaction, atropine blocks the cholinomimetic effects of the agonist during both this state and its otherwise subsequent irreversible state.

Animals↗
PubMed1987

Kinetics of solvolysis and muscarinic actions of an N-methyl-N-(2-bromoethyl)amino analogue of oxotremorine.

An N-methyl-N-(2-bromoethyl)amino analogue (2) of oxotremorine cyclized in phosphate buffer to an aziridinium ion (3). The first-order rate constants (k1) for the cyclization reaction at 22 and 37 degrees C (pH 7.3) were 0.14 and 0.85 min-1, respectively. Determination of k1 as a function of pH gave a pKa value of 5.6 for 2. The rate constants (k2) for the hydrolysis of 3 at 22 and 37 degrees C (pH 7.3) were 0.0083 and 0.040 min-1, respectively. Compound 3 was 3-fold more active than oxotremorine as a muscarinic agonist on the guinea pig ileum, whereas its nicotinic actions, as estimated on the frog rectus, were quite weak. Because of its greater rate of cyclization and the higher peak concentrations of the aziridinium ion which ensue, 2 may offer advantages over its (2-chloroethyl)amino analogue (1) as an alkylating ligand for muscarinic receptors.

Animals↗