Experiments in the Synthesis of Pyridinium Amidines and Imino Esters

Poziomek, Edward J.

doi:10.1021/jo01037a521

Cited by 13 publications

(8 citation statements)

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“…4-Aminopyridine methiodide, a permanently charged analogue of 4-AP, was made by the method described by Poziomek (1963 Colquhoun, 1971) to a rectangular hyperbola of the form: In previous studies, primarily in the squid giant axon (Yeh, Oxford, Wu & Narahashi, 1976a, b;Meves & Pichon, 1977), it was assumed that all of the delayed outward current was sensitive to block by the aminopyridines and that the slower activation kinetics of the outward current in the presence of the aminopyridines reflected unblocking of the channel during the test depolarization (as the result of the decreased affinity of the aminopyridines at positive membrane potentials). Our previous analysis (Howe & Ritchie, 1988) (Howe & Ritchie, 1988) Meves & Pichon, 1977).…”

Section: Methodsmentioning

confidence: 99%

“…The following aminopyridines were tested: 2-aminopyridine, 3-aminopyridine, 3,4-diaminopyridine (all obtained from Sigma), and 4-aminopyridine (obtained both from Sigma and Aldrich). 4-Aminopyridine methiodide, a permanently charged analogue of 4-AP, was made by the method described by Poziomek (1963). All results were obtained at room temperature (22°C) and at times at which steady-state responses to the drug applications were obtained.…”

Section: Introductionmentioning

confidence: 99%

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On the active form of 4‐aminopyridine: block of K+ currents in rabbit Schwann cells.

Howe

Ritchie

1991

The Journal of Physiology

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SUMMARY1. The blocking action of 4-aminopyridine (4-AP) on the outward potassium currents evoked by depolarization of rabbit Schwann cells in short-term primary culture was studied with the whole-cell configuration of the patch-clamp method.2. We have determined the apparent equilibrium dissociation constant, K, for the action of 4-AP to block potassium currents at a series of different extracellular and intracellular pH values. 4-Aminopyridine is an organic base and exists in both charged and uncharged forms in aqueous solution. Changes in the pH of the extracellular and intracellular solutions therefore also change the extracellular and intracellular proportions of these two forms, and the values of K that were obtained were found to depend in a consistent way on both the extracellular and the intracellular pH.3. At alkaline extracellular pH, K was decreased. At acidic extracellular pH, K was increased. In contrast, increasing the intracellular pH from 7-2 to 8-1 reduced the apparent potency of extracellularly applied 4-AP (i.e. increased K), and decreasing the intracellular pH (to 6 4) increased this apparent potency (i.e. decreased K).4. The 4-AP analogues, 2-aminopyridine, 3-aminopyridine and 3,4-diaminopyridine, were also tested. At half-block of the potassium current, the intracellular concentration of the cationic form of the various aminopyridines (applied extracellularly at pH 7 2) varied by a factor of less than five, whereas that of the uncharged form varied by a factor of over 700.5. The results are inconsistent with the hypothesis that the cationic form of the aminopyridines, acting from the extracellular solution, contributes in any substantial way to potassium channel block. It also seems unlikely that the uncharged form, acting either extracellularly or intracellularly, is solely responsible for the block. However, the results as a whole are consistent with the idea that it is the cation acting from the intracellular side that blocks the 4-AP-sensitive potassium channel and that the affinity with which 4-AP blocks the channel depends on the intracellular pH. The results would be explained if the cation competes with protons for a binding site that has an apparent pKa of about 7 0.6. The results, nevertheless, are not inconsistent with the possibility that both the uncharged form and the intracellular charged form of 4-AP are active in blocking the 4-AP-sensitive potassium channel. This can only be so, however, if the uncharged MS 8358

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

On the active form of 4‐aminopyridine: block of K+ currents in rabbit Schwann cells.

Howe

Ritchie

1991

The Journal of Physiology

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“…Aminopyridines (Aldrich Chemical Co., Milwaukee, WI) were added to the SIS. 4-aminopyridine methiodide (4APMI) was prepared by the method of Poziomek (1963), and had a melting point of 179-1800C. All experiments were performed at a constant temperature of 8-10°C.…”

Section: Methodsmentioning

confidence: 99%

Modulation of aminopyridine block of potassium currents in squid axon

Kirsch¹,

Yeh²,

Oxford³

1986

Biophysical Journal

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Aminopyridines are known to block potassium (K) currents in excitable membranes in a manner dependent upon membrane potential, such that the block is relieved by depolarization and restored upon repolarization. In the present study, the effects of aminopyridines on voltage-dependent potassium (K) channels were examined in internally perfused, voltage-clamped squid giant axons. The time course of block restoration after conditioning depolarization was found to be modulated by membrane electric field, K-channel gating, and external cations. Depolarized holding potentials accelerated block restoration without altering steady-state block levels, suggesting that the voltage dependence of block restoration may be related to K channel gating rather than drug binding per se. In support of this notion, low external calcium concentration, which shifts the voltage dependence of K-channel gating to more negative potentials, also accelerated block restoration. Conversely, the relationship between the rate of block restoration and membrane holding potential was shifted in the depolarizing direction by phloretin, an agent that shifts the dependence of K-channel opening on membrane potential in a similar manner. Modification of K-channel gating also was found to alter the rate of block restoration. Addition of internal zinc or internal treatment with glutaraldehyde slowed the time course of both K-channel activation and aminopyridine block restoration. Aminopyridines also were found to interact in the K channel with external Cs+, NH4+, and Rb+, each of which slowed aminopyridine block restoration. Our results suggest that aminopyridines enter and occlude K channels, and that the availability of the binding site may be modulated by channel gating such that access is limited by the probability of the channel reaching an intermediate closed state at the resting potential.

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“…1-Methyl-4-aminopyridinium iodide (4-APMI) was prepared according to the method of Poziomek (1963). After recrystallization twice from absolute ethanol it had a m.p.…”

Section: Drugsmentioning

confidence: 99%

A Comparison of the Facilitatory Actions of 4‐aminopyri‐dine Methiodide and 4‐aminopyridine on Neuromuscular Transmission

Horn

Lambert

Marshall

1979

British J Pharmacology

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4‐Aminopyridine methiodide (4‐APMI), a quaternary analogue of aminopyridine (4‐AP), was tested for neuromuscular facilitatory actions on the chick biventer cervicis and frog sartorius nerve‐muscle preparations. In the chick, 4‐APMI (10−4 to 10−2m) augmented indirectly elicited twitches and reversed tubocurarine‐induced neuromuscular block. Reversal of tubocurarine block was observed after treatment of the muscle with an anticholinesterase. 4‐APMI did not itself produce contracture but augmented responses to added acetylcholine. 4‐APMI (10−4m) prolonged the time courses of endplate potentials (e.p.ps) and miniature end‐plate potentials (m.e.p.ps) in the frog. 4‐APMI (10−4m) increased e.p.p. quantal content. 4‐AP was about 100 times more active than 4‐APMI in increasing quantal content. Both compounds prolonged muscle action potentials at similar concentrations. 4‐APMI (10−3 to 3 × 10−3m) possessed anticholinesterase activity in homogenates of chick biventer cervicis muscle. It is concluded that 4‐APMI increases evoked acetylcholine release and also possesses a weak anticholinesterase action. The greater action of 4‐AP on quantal content is probably due to an intracellular action, possibly involving the release of calcium ions.

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Experiments in the Synthesis of Pyridinium Amidines and Imino Esters

Cited by 13 publications

References 1 publication

On the active form of 4‐aminopyridine: block of K+ currents in rabbit Schwann cells.

On the active form of 4‐aminopyridine: block of K+ currents in rabbit Schwann cells.

Modulation of aminopyridine block of potassium currents in squid axon

A Comparison of the Facilitatory Actions of 4‐aminopyri‐dine Methiodide and 4‐aminopyridine on Neuromuscular Transmission

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