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At least 19 recordsLinked to original sources
PubMed1979

[Comparison of 2-aminopyridine, 3-aminopyridine and 4-aminopyridine hydrochlorides and iodomethylates by the degree of decrease in curare toxicity].

The authors carried out studies on rats with apnoea, indiced by (+)-tubucurarine and found protective action, due to galantamine, neostigmine, hydrochlorides and jodometilates of 2-aminopyridine, 3-aminopyridine and 4-aminopyridine. Jodmethylates had protective action in larger doses in comparison with the respective hydrochlorides of nonsubstituted pyridilamines. The authors proposed a method for determination and comparison of the effect of compounds, eliminating the action of antidepolarizating myorelaxants, on tubocurarine toxicity.

Aminopyridines↗
PubMed2001

Aminopyridines for symptomatic treatment in multiple sclerosis.

BACKGROUND: Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have been proposed as a symptomatic therapy for people with multiple sclerosis (MS). OBJECTIVES: To determine the efficacy and safety of aminopyridines in improving neurological deficits in people with MS. SEARCH STRATEGY: Computerised general (MEDLINE, EMBASE) and specialised databases (Cochrane MS Group's trials register, CCTR). Hand search of bibliographic references from retrieved studies and recent MS symposia reports. Contact with principal investigators of known studies. SELECTION CRITERIA: Trials were included if they fulfilled all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints. DATA COLLECTION AND ANALYSIS: We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from the 16 studies available as full papers. MAIN RESULTS: Five studies (six publications) and 144 participants were considered in this review. Two more abstracts are awaiting assessment. All five studies were single-centre, double-blind, crossover trials. Four studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. The duration of treatment ranged from hours to three months. The median quality score of the studies was 3 (range 2-5). The heterogeneity of outcome assessment and the absence of information on individual study periods, allowed quantitative pooling of results for few categorical variables. Of the 144 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Manual muscle testing was assessed in three studies (54 patients), with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Ambulation was assessed in three studies (54 patients): 9 patients (17%) improved during study treatment versus none during placebo (p<0.001). An improvement in EDSS score was found in 13 of the 144 participants during study treatment (9%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in the two trials that evaluated cognitive function. Finally, 47 of 136 people with MS (35%) felt improved when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0). REVIEWER'S CONCLUSIONS: Based on currently available information, no unbiased statement can be made about the safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs involving more than 300 participants. We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.

4-Aminopyridine↗
PubMedDate not supplied

Syntheses and electronic spectroscopy of [PtL(L')][ClO4] complexes (HL = 6-phenyl-2,2'-bipyridine; L' = pyridine, 4-aminopyridine, 2-aminopyridine, and 2,6-diaminopyridine).

Four cyclometalated Pt(II) complexes, [PtL(L')][ClO4] [HL = 6-phenyl-2,2'-bipyridine; L' = pyridine (1), 4-aminopyridine (2), 2-aminopyridine (3), 2,6-diaminopyridine (4)], were designed and synthesized to probe intramolecular N...Pt interactions. The crystal structures of the compounds show that the pyridine ligands are almost perpendicular to the planes of the molecules. In addition, the pendant NH2 groups of the 2-aminopyridine and 2,6-diaminopyridine ligands are close to the metal centers in complexes 3 and 4, with the Pt-N(H2) distances (3.065(3)-3.107(3) A) significantly shorter than the sum of the van der Waals radii of Pt and N. These compounds were also studied by electronic spectroscopy. All the complexes display intense intraligand pi-->pi* transitions at 200-340 nm (epsilon = 10(4)-10(3) M-1 cm-1) and moderately intense (epsilon approximately 10(3) M-1 cm-1) metal (Pt)-to-ligand (pi*) charge-transfer (MLCT) transitions. For 1 and 2, the MLCT transitions occur at approximately 390 nm, but the MLCT transition of 4 is exceptionally low in energy (492 nm). The low-temperature emission spectra of the complexes in frozen EMD glass indicate that 3 pi pi* is the emissive excited state for 1 and 2 but the emission of 3 is from a 3MLCT excited state. On the basis of the spectroscopic results, the order of energy of the MLCT excited states is established as 1 approximately 2 > 3 > 4. It is proposed that the red shifts of the MLCT transitions in 3 and 4 are due to increased electron-donating abilities of the ancillary pyridine ligands and intramolecular interactions between the orbitals of amine nitrogen lone pairs. Crystal data for the complexes are as follows. 1: triclinic P1, Z = 2, a = 8.7917(2) A, b = 10.6398(3) A, c = 11.9592(3) A, alpha = 107.130(1) degrees, beta = 92.522(1) degrees, gamma = 111.509(1) degrees. 2.CH3CN: triclinic P1, Z = 2, a = 7.0122(4) A, b = 12.9653(8) A, c = 14.0283(9) A, alpha = 107.3100(10) degrees, beta = 102.7640(10) degrees, gamma = 91.6320(10) degrees. 3.CH3CN: triclinic P1, Z = 2, a = 7.6459(1) A, b = 10.8433(1) A, c = 14.8722(2) A, alpha = 99.383(1) degrees, beta = 93.494(1) degrees, gamma = 101.385(1) degrees. 4.CH3CN: triclinic P1, Z = 2, a = 7.862(2) A, b = 10.977(3) A, c = 14.816(5) A, alpha = 99.34(2) degrees, beta = 92.64(2) degrees, gamma = 104.11(2) degrees.

Journal Article↗
PubMed1985

Neocortical cytopathology in focal aminopyridine seizures as related to the intracortical diffusion of [3H] 4-aminopyridine. Electrophysiologic and light-microscopic studies.

Focal seizure was induced in rat and cat neocortex by the topical application of aminopyridines. The epileptic character of the focal events was followed by surface and intracellular recordings of seizure activity. The pathologic alterations in the neurons, the glial cells, and the protein permeability of the neocortical blood vessels were investigated by means of light microscopy, using standard histological stainings and immunohistochemical detection of endogenous serum albumin. Diffusion of [3H] 4-aminopyridine in the neocortex was studied by light-microscopic autoradiography. The spreading of the neuropathologic changes strictly followed the diffusion of the tritiated compound, suggesting the gradual involvement of neocortical layers in the seizure process.

4-Aminopyridine↗
PubMed1981

Cholinergic effect of 4-aminopyridine and adrenergic effect of 4-methyl-2-aminopyridine in cardiac muscle.

The effect of 4-aminopyridine (4AP) and 4-methyl-2-aminopyridine (4M2AP), 10(-3) M, was studied on isolated spontaneously beating right atria and electrically driven left atria of the rabbit and the cat. In the rabbit preparations, 4AP had a positive inotropic effect which was unaffected by propranolol or atropine, and a negative chronotropic effect which was abolished by atropine. In the cat, 4AP decreased both force and rate, and these effects were reversed when 4AP was repeated in the presence of atropine. In contrast, 4M2AP increased the rate and force of contraction in both species. These effects were reduced but not abolished when 4M2AP was repeated in the presence of propranolol. It is concluded that 4AP has a cholinergic effect presumably mediated by acetylcholine release which predominates over its direct positive inotropic effect in the rabbit but not in the cat, and which is responsible for its effect on rate in both species. 4M2AP also has a direct positive inotropic action, but its marked effects on force and rate of contraction are largely due to noradrenaline release. The selectivity of 4AP for cholinergic and 4M2AP for noradrenergic transmission suggests that there are differences in potassium channels or in calcium uptake or release mechanisms in the respective nerve terminals.

4-Aminopyridine↗
PubMed1989

Distribution of the 4-aminopyridine derivative 3-methoxy-4-aminopyridine in mice.

The tissue distribution of [14C]3-Methoxy-4-aminopyridine was studied after intravenous administration in mice using whole body and microautoradiography. Dense accumulation was found in cholinergically innervated, secretory organs. High radioactivity was detected in the adrenal medulla suggesting that the observed excitement and hyperglycemia are due to the stimulation of catecholamine secretion. [14C]3-Methoxy-4-aminopyridine quickly passes the blood brain barrier and predominantly accumulates in the hippocampus, the thalamic nuclei and the cortex.

4-Aminopyridine↗
PubMed1979

A comparison of the facilitatory actions of 4-aminopyridine methiodide and 4-aminopyridine on neuromuscular transmission.

1 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. 2 In the chick, 4-APMI (10(-4) to 10(-2) M) 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. 3 4-APMI (10(-4) M) prolonged the time courses of endplate potentials (e.p.ps) and miniature endplate potentials (m.e.p.ps) in the frog. 4 4-APMI (10(-4) M) 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. 5 4-APMI (10(-3) to 3 X 10(-3) M) possessed anticholinesterase activity in homogenates of chick biventer cervicis muscle. 6 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.

Action Potentials↗
PubMedDate not supplied

Oxidation and cleavage of 3-aminopyridine adenine dinucleotide phosphate with periodate.

Treatment of 3-aminopyridine adenine dinucleotide phosphate with sodium periodate in the neutral pH resulted in oxidation of the ribose linked to 3-aminopyridine and cleavage of the dinucleotide into adenosine- and 3-aminopyridine-containing moieties. Separation of these moieties was afforded by thin-layer chromatography, high-performance liquid chromatography, and fast protein liquid chromatography. From fast atom bombardment mass spectra and nuclear magnetic resonance spectra, the adenosine-containing moiety was identified as 2'-phosphoadenosine 5'-phosphate while the aminopyridine moiety was present in a mixture of the hydrated 3-aminopyridine mononucleotide/nucleoside dialdehyde. Separation of the completely oxidized product by Pharmacia fast protein liquid chromatography gave three major peaks corresponding to 2'-phosphoadenosine 5'-phosphate, 2'-phosphoadenosine 5'-diphosphate and oxidized 3-aminopyridine nucleoside, with minor amount of oxidized 3-aminopyridine mononucleotide. Thus the oxidized 3-aminopyridine adenine dinucleotide phosphate was shown to cleave by two pathways: it may either undergo beta-elimination to give 2'-phosphoadenosine 5'-diphosphate and oxidized 3-aminopyridine nucleoside; or the phosphodiester linkage may be hydrolyzed to give 2'-phosphoadenosine 5'-phosphate and oxidized 3-aminopyridine mononucleotide. The latter compound may further undergo beta-elimination and eventually give oxidized 3-aminopyridine nucleoside. Hydrolysis could be prevented by storing the sample as lyophilized powder, while beta-elimination was diminished by lowering the storage temperature. We found that the lyophilized powder of oxidized 3-aminopyridine adenine dinucleotide phosphate can be stored at -50 degrees C for several months with minimum decomposition.

Chromatography, High Pressure Liquid↗
PubMed1990

Adsorption of aminopyridines to phosphatidylserine membranes.

Aminopyridines belong to the class of compounds which facilitate synaptic transmission at low calcium concentration, an effect associated with the block of K+ channels, enhanced entry of calcium into presynaptic terminals and greater release of transmitter. We have measured the zeta-potential of phosphatidylserine vesicles in the presence of aminopyridines and some related compounds in order to relate the strength of association of the aminopyridines with their biological effectiveness. The dependence of zeta-potential on the concentration of aminopyridines was analyzed in terms of the Langmuir-Stern-Grahame adsorption model. The rank order of the association constants (in M-1) obtained in the study was as follows: 3,4-diaminopyridine (6.5), 4,5-diaminopyrimidine (3.8), 4-aminopyridine (2.6), 3-aminopyridine (1.8), 2-aminopyridine (1.6), 4-dimethylaminopyridine (0.5), 4-aminopyridine methiodide (0.2), and, as control, calcium (12.1). The comparison of association constants with published results of the electric potential maps obtained by the CNDO/2 method suggests that binding to phosphatidylserine membrane increases with the density of excess charge on the protonated aminopyridine ring. We find that the sequence of potencies of aminopyridines in blocking K+ channels, in releasing transmitter, and in the shifts of calcium concentration dependence of synaptic transmission are about the same as the sequence of association constants with the phosphatidylserine membrane. Assuming that the binding domain for aminopyridines in the presynaptic terminal has similar adsorption properties as the phosphatidylserine membrane, we estimate the electric potential difference between the domain and the external solution to be between -300 and -340 mV.

Adsorption↗
PubMed1982

Effect of 4-aminopyridine on end-plate receptor desensitization caused by carbachol.

The effect of 4-aminopyridine on receptor desensitization was investigated in the isolated rat diaphragm by measuring transmembrane potential in the end-plate region. When 4-aminopyridine was added to the bath before carbachol, the depolarization produced by the agonist was permanent, that is 4-aminopyridine completely inhibited the receptor desensitization produced by prolonged exposure of the receptors to carbachol. When it was added after carbachol in the phase in which the membrane had already repolarized, the end-plate region depolarized. Therefore, 4-aminopyridine was also able to reverse the receptors from the desensitized state to the resting non-desensitized one. The effect of 4-aminopyridine was concentration-dependent. Calcium antagonized the effect of 4-aminopyridine. 4-Aminopyridine also reversed the receptors from their desensitized state to the resting one in the isolated and chronically denervated rat hemidiaphragm. The known action of the aminopyridines cannot explain the effect of 4-aminopyridine described here. It is suggested that it is caused by an action on either the receptor-ionic channel complex or the lipids of the postjunctional membrane surrounding it.

4-Aminopyridine↗
PubMed1999

Functional effects of 4-aminopyridine (4-AP) on pulmonary and systemic vessels from normoxic control and hypoxic pulmonary hypertensive rats.

The effects of the outward rectifying potassium channel blocker, 4-aminopyridine, on contractile tone and on contractile responses to the spasmogens, 5-hydroxytryptamine and endothelin-1, were examined in pulmonary arteries (main and intralobar) and systemic vessels (aorta and mesenteric artery) from rats with and without hypoxic pulmonary hypertension. Hypoxic pulmonary hypertension was induced by exposure of rats to 10% oxygen for 1 week. The development of pulmonary hypertension was associated with (i) depolarization of the cell membrane in intralobar pulmonary artery, but not aorta, and (ii) an increase in sensitivity to 5-hydroxytryptamine in pulmonary, but not systemic, vessels; sensitivity to endothelin-1 was unchanged. 4-Aminopyridine contracted all of the vessels studied. In pulmonary hypertension the sensitivity to 4-aminopyridine was increased ten-fold in pulmonary vessels but was unchanged in systemic vessels. Threshold concentrations of 4-aminopyridine (< or =3x10(-3) M) augmented contractions to 5-hydroxytryptamine in main pulmonary artery and aorta from control rats but failed to augment contractions to 5-hydroxytryptamine in main pulmonary artery from pulmonary hypertensive rats. Responses to endothelin-1 were not augmented by 4-aminopyridine. The membrane depolarization and the increases in sensitivity to 4-aminopyridine and 5-hydroxytryptamine seen in pulmonary hypertension are compatible with the concept that potassium channel function is altered in pulmonary, but not systemic, vessels from pulmonary hypertensive rats. Our data suggest that in main pulmonary artery a common mechanism is responsible for (i) the augmentation of 5-hydroxytryptamine responses by 4-aminopyridine in control rats, and (ii) the sensitization to 5-hydroxytryptamine seen in pulmonary hypertensive, compared with control, rats in the absence of 4-aminopyridine. Hence, we conclude that the sensitization to 5-hydroxytryptamine may be due to downregulation of 4-aminopyridine-sensitive potassium channels.

4-Aminopyridine↗
PubMed2002

The nature of the receptor site for the reversible K+ channel blocking by aminopyridines.

This work presents a theoretical study aimed at the identification of the receptor site for the blocking of the voltage dependent K+ channels by protonated aminopyridines. Thus, the density functional theory (DFT) at the B3LYP/6-311 G (d,p) level is applied, both in vacuum and in solution, to a series of active (protonated) compounds: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. Analysis of the X-ray structure of the alpha-subunit of the channel shows that charged aminopyridines can interact electrostatically with a glutamic acid residue in the outside of the pore, or through a cation-pi interaction in the inside. To test both possibilities, model complexes are built using as nucleophiles a carboxylic group and an ethylene molecule, respectively. The three-dimensional electrostatic potential distribution of the protonated aminopyridines shows that an approaching nucleophile will be oriented toward the N-H (protonated) bond. Interaction with the carboxylic residue leads to a proton transfer, with the aminopyridine-carboxylic acid linked by a hydrogen bond. The observed breaking of the equivalence of the Laplacian of the charge density, the relative energy variation for the complexes, and the interaction with only one of the carboxylic residues in the fourfold alpha-subunit of the K+ channel are not compatible with the observed in vitro activity variation of aminopyridines. On the other hand, the study on the ethylene complexes shows, in vacuum and solution, a cation-pi interaction, clearly characterized by the atoms in molecules (AIM) theory. The variation of relative energy in solution is very small, but approaches the variation of in vitro activity. Our results, the pharmacophoric characteristics of aminopyridines, and the analysis of the three-dimensional internal structure of the K+ channel alpha-subunit suggest two putative receptor sites. One is formed by the four Thr-Thr-Val chains conforming the entrance to the narrow part of the inner K+ channel. The other is defined by four Thr residues within the pore.

Amino Acid Sequence↗
PubMed2000

Seizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: role of glutamate- and GABA-mediated neurotransmission and of ion channels.

Infusion of the K(+) channel blocker 4-aminopyridine in the hippocampus induces the release of glutamate, as well as seizures and neurodegeneration. Since an imbalance between excitation and inhibition, as well as alterations of ion channels, may be involved in these effects of 4-aminopyridine, we have studied whether they are modified by drugs that block glutamatergic transmission or ion channels, or drugs that potentiate GABA-mediated transmission. The drugs were administered to anesthetized rats subjected to intrahippocampal infusion of 4-aminopyridine through microdialysis probes, with simultaneous collection of dialysis perfusates and recording of the electroencephalogram, and subsequent histological analysis. Ionotropic glutamate receptor antagonists clearly diminished the intensity of seizures and prevented the neuronal damage, but did not alter substantially the enhancement of extracellular glutamate induced by 4-aminopyridine. None of the drugs facilitating GABA-mediated transmission, including uptake blockers, GABA-transaminase inhibitors and agonists of the A-type receptor, was able to reduce the glutamate release, seizures or neuronal damage produced by 4-aminopyridine. In contrast, nipecotate, which notably increased extracellular levels of the amino acid, potentiated the intensity of seizures and the neurodegeneration. GABA(A) receptor antagonists partially reduced the extracellular accumulation of glutamate induced by 4-aminopyridine, but did not exert any protective action. Tetrodotoxin largely prevented the increase of extracellular glutamate, the electroencephalographic epileptic discharges and the neuronal death in the CA1 and CA3 hippocampal regions. Valproate and carbamazepine, also Na(+) channel blockers that possess general anticonvulsant action, failed to modify the three effects of 4-aminopyridine studied. The N-type Ca(2+) channel blocker omega-conotoxin, the K(+) channel opener diazoxide, and the non-specific ion channel blocker riluzole diminished the enhancement of extracellular glutamate and slightly protected against the neurodegeneration. However, the two former compounds did not antagonize the 4-aminopyridine-induced epileptiform discharges, and riluzole instead markedly increased the intensity and duration of the disharges. Moreover, at the highest dose tested (8mg/kg, i.p.), riluzole caused a 75% mortality of the rats. We conclude that 4-aminopyridine stimulates the release of glutamate from nerve endings and that the resultant augmented extracellular glutamate is directly related to the neurodegeneration and is involved in the generation of epileptiform discharges through the concomitant overactivation of glutamate receptors. Under these conditions, a facilitated GABA-mediated transmission may paradoxically boost neuronal hyperexcitation. Riluzole, a drug used to treat amyotrophic lateral sclerosis, seems to be toxic when combined with neuronal hyperexcitation.

4-Aminopyridine↗
PubMed1989

Differential effects of 4-aminopyridine on acetylcholine release triggered by K+ depolarization, veratridine, or A23187 in rat cerebral cortical synaptosomes.

The effect of 4-aminopyridine on [3H]acetylcholine release was studied in rat cerebral cortical synaptosomes in the presence of a several secretagogues that have different mechanisms of action. As found previously, 4-aminopyridine increased [3H]acetylcholine release in a concentration-dependent manner (5-10 mM); a high concentration (10 mM) also elevated [3H]choline efflux. However, the 35 mM K+ induced release of [3H]acetylcholine was attenuated by 4-aminopyridine at concentrations (less than 5 mM) that had no effect on transmitter release. At no concentration of 4-aminopyridine was the release of transmitter additive with 35 mM K+ induced release. Veratridine-induced release was neither attenuated nor additive with low concentrations of 4-aminopyridine, even when a sub-maximal concentration of the sodium ionophore was used (10 microM). In contrast, A23187-induced release was additive with that caused by 4-aminopyridine. These results suggest that: 1) 4-aminopyridine blocks potassium channels involved in regulating membrane potential in isolated cholinergic terminals; and 2) changes in the activity of these 4-aminopyridine sensitive K+ channels are not important in the nerve terminal's response to depolarization caused by sodium influx.

4-Aminopyridine↗
PubMed1985

Mechanism of the calcium-dependent stimulation of transmitter release by 4-aminopyridine in synaptosomes.

The mechanism of the Ca2+-dependent stimulation of neurotransmitter release by 4-aminopyridine in synaptosomes was studied. The stimulation of gamma-[3H]aminobutyric acid and [3H]acetylcholine release by 4-aminopyridine was not significantly affected either by tetrodotoxin or by the absence of Na+ in the medium, whereas the toxin notably inhibited the release of both transmitters induced by veratridine. On the other hand, the release of labeled gamma-aminobutyric acid induced by 4-aminopyridine was inhibited by both La3+ and ruthenium red, two blockers of Ca2+ transport in synaptosomes. In other experiments, 4-aminopyridine had only a slight stimulatory effect, if any, on the influx of 45Ca2+ into synaptosomes, under both resting and K+-depolarizing conditions. Ruthenium red inhibited the stimulation by K+ of the 45Ca2+ uptake, and 4-aminopyridine did not antagonize this inhibition. We conclude that the transmitter-releasing action of 4-aminopyridine in synaptosomes does not involve an excitatory effect on the membrane which may result in the opening of voltage-sensitive Na+ channels. 4-Aminopyridine does not seem to act either by enhancing Ca2+ entry into the synaptosomes. It is proposed that 4-aminopyridine facilitates the coupling between Ca2+ binding and transmitter secretion at the presynaptic membrane.

4-Aminopyridine↗
PubMed1985

[Presynaptic effects of aminopyridines on the neuromuscular junction of vertebrates].

In this review the effects of aminopyridines and chemically related compounds are documented in an attempt to analyse the mechanism underlying their presynaptic actions at the vertebrate neuromuscular junction. Aminopyridines and related compounds are of particular interest because they greatly increase the amount of acetylcholine released in response to both conducted nerve impulses and electrotonic depolarizations of tetrodotoxin blocked motor nerve terminals. The apparent rank order of potency for increasing quantal transmitter release evoked by nerve impulse at physiological pH was as follows: 3,4-diaminopyridine greater than 4-aminopyridine greater than 4-aminoquinoline greater than 3-aminopyridine greater than 2,6-diaminopyridine greater than 2-aminopyridine greater than 4-nitropyridine greater than 4-aminopyridine N-oxyde greater than 4-hydroxypyridine greater than 2,4-dihydroxypyridine. The fact that both pyridine and aniline were found to be inactive indicate that both a pyridine ring and an amino-substituent are necessary for activity. A common site of action for the drugs here reported should be rationalized on the basis that their protonated molecular forms generate a common electrostatic potential field pattern. This results together with those concerning the dependence of pyridine activity on extracellular pH leads to the conclusion that this family of compounds exert its activity at the internal face of the motor nerve terminal membrane. Aminopyridines in concentrations that increase transmitter release evoked by nerve impulses block potassium conductance in motor nerve terminals and lengthen the presynaptic action potential, this effect leads to an enhanced calcium influx and consequently to an increase in acetylcholine release. The fact that aminopyridines had no consistent effect on transmitter release at junctions depolarized by elevated potassium ions strongly supports the view that these drugs have no direct effect on voltage-dependent calcium channels and that their primary site of action is on voltage-sensitive potassium channels of motor nerve terminals.

4-Aminopyridine↗