Dihydropyridine Structure Research Articles

Virtual screening of some heterocyclic structures toward novel antibacterial agents

Infectious diseases and their treatment are among the most important issues in global health and economy. Moreover, increasing prevalence of antibiotic-resistant pathogenic bacteria necessitates the considerable need for discovering new drugs. Some heterocyclic structures with dihydropyridine (DHP) scaffold have been reported as antimicrobial agents. Herein, we report a structure-based virtual screening of a pool of 3,5-disubstituted DHPs and a post-analysis of virtual hits through in vitro antibacterial assessment. Four top-ranked DHP structures (6a–d) were found to interact with the relevant target active sites and exhibited superior stereoelectronic features within their enzyme inhibition. Selected compounds were synthesized and assessed for their antibacterial activity via microdilution method. Results of this study represented a significant application of multi-step virtual screening strategy in identifying privileged DHP structures as good starting points for further developments toward more potent antibacterial agents.

Malondialdehyde–acetaldehyde adduct is the dominant epitope after MDA modification of proteins in atherosclerosis

Antibodies to malondialdehyde (MDA)-modified macromolecules (adducts) have been detected in the serum of patients with atherosclerosis and correlate with the progression of this disease. However, the epitope and its formation have not been characterized. Studies have shown that excess MDA can be degraded to acetaldehyde, which combines with proteins to from a stable dihydropyridine adduct. To investigate, mice were immunized with MDA adducts in the absence of adjuvant and showed an increase in antibodies to MDA adducts and the carrier protein as the concentration of MDA was increased. In fact, a number of the commercially available antibodies to MDA-modified proteins were able to be inhibited by a chemical analogue, hexyl-MAA. Also, MDA–MAA adducts were detected in the serum and aortic tissue of JCR diabetic/atherosclerotic rats. These studies determined that commercially available antibodies to MDA predominantly react with the MAA adduct and are present in the JCR model of atherosclerosis in both the serum and the aortic tissue. Therefore, the immune response to MDA-modified proteins is most probably to the dihydropyridine structure (predominant epitope in MAA), which suggests that MAA adducts may play a role in the development and/or progression of atherosclerosis.

Study of 1,4-Dihydropyridine Structural Scaffold: Discovery of Novel Sirtuin Activators and Inhibitors

NAD(+)-dependent sirtuin deacetylases have emerged as potential therapeutic targets for treatment of human illnesses such as cancer, metabolic, cardiovascular, and neurodegenerative diseases. The benefits of sirtuin modulation by small molecules have been demonstrated for these diseases. In contrast to the discovery of inhibitors of SIRT1, -2, and -3, only activators for SIRT1 are known. Here, we rationalized the potential of the previously unexplored dihydropyridine scaffold in developing sirtuin ligands, thus we prepared a series of 1,4-dihydropyridine-based derivatives 1-3. Assessment of their SIRT1-3 deacetylase activities revealed the importance of the substituent at the N1 position of the dihydropyridine structure on sirtuin activity. Placement of cyclopropyl, phenyl, or phenylethyl groups at N1 conferred nonselective SIRT1 and SIRT2 inhibition activity, while a benzyl group at N1 conferred potent SIRT1, -2, and -3 activation. Senescence assays performed on hMSC and mitochondrial function studies conducted with murine C2C12 myoblasts confirmed the compounds' novel and unique SIRT-activating properties.

Bay w 9798, a Dihydropyridine Structurally Related to Nifedipine with No Calcium Channel-blocking Properties, Inhibits Tumour Necrosis Factor-α-induced Vascular Cell Adhesion Molecule-1 Expression in Endothelial Cells by Suppressing Reactive Oxygen Species Generation

Dihydropyridine-based calcium antagonists (DHPs) are widely used to treat hypertension. We have previously shown that nifedipine, one of the most popular DHPs, blocks tumour necrosis factor-alpha (TNF-alpha)-induced monocyte chemoattractant protein-1 as well as vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells by suppressing reactive oxygen species generation (ROS). The molecular mechanism is still to be elucidated, however, because endothelial cells do not possess voltage-operated L-type calcium channels. The aim of this study was to determine in TNF-alpha-exposed human umbilical vein endothelial cells (HUVECs) whether and how Bay w 9798, a dihydropyridine structurally related to nifedipine with no calcium antagonistic properties, may suppress VCAM-1 expression, a key molecule which mediates the adhesion of monocytes to vasculature in the early stages of atherosclerosis. In HUVECs, 10 ng/ml TNF-alpha for 4 h stimulated ROS generation and subsequently upregulated VCAM-1 mRNA levels, both of which were dose-dependently blocked by Bay w 9798. The results demonstrated that Bay w 9798 inhibited VCAM-1 expression in TNF-alpha-exposed cells by suppressing ROS generation. They suggest that the anti-inflammatory and anti-oxidative properties of nifedipine and Bay w 9798 may be ascribed to the dihydropyridine structure, which is common to both molecules and has no calcium antagonistic ability.

Reactions of heterocumulenes with organometallic reagents: XIV. Quantum-chemical study on the mechanism of unusual thermally induced transformation of methyl N-Methylbuta-2,3-dienimidothioates into iminocyclobutenes with migration of the methylsulfanyl group

The mechanism of formation of cyclobutene ring from methyl 2-methoxy-and 2-phenyl-N-methylbuta-2,3-dienimidothioates (H2C=C=C(R)-C(SMe)=NMe, 1-aza-1,3,4-trienes) was studied by quantum-chemical methods. The limiting stage in the [1,3]-sigmatropic migration of the methylsulfanyl group was found to follow a reaction path involving a “collapsed” state of the azatriene with linear configuration of the C=N-Me fragment, which is characterized by reduced activation barrier. The results of calculations substantiate preferential formation of pyrrole and dihydropyridine heterorings in the thermolysis of methyl 2-methoxy-N-methylbuta-2,3-dienimidothioate and of dihydropyridine and cyclobutene structures in the thermolysis of methyl N-methyl-2-phenylbuta-2,3-dienimidothioate.

Efonidipine hydrochloride: a dual blocker of L- and T-type ca(2+) channels.

T-type Ca(2+) channels have properties different from those of the L-type and are involved in cardiac pacemaking and regulation of blood flow, but not in myocardial contraction. Efonidipine is an antihypertensive and antianginal drug with dihydropyridine structure that was recently found to block both L- and T-type Ca(2+) channels. In isolated myocardial and vascular preparations, efonidipine has potent negative chronotropic and vasodilator effects but only a weak negative inotropic effect. In experimental animals and patients, reduction of blood pressure by the drug was accompanied by no or minimum reflex tachycardia leading to improvement of myocardial oxygen balance and maintenance of cardiac output. Efonidipine increased glomerular filtration rate without increasing intraglomerular pressure. By relaxing both the afferent and efferent arterioles, efonidipine markedly reduced proteinuria. Thus, efonidipine, an L- and T-type dual Ca(2+) channel blocker, appears to have an ideal profile as an antihypertensive and antianginal drug with organ-protective effects in the heart and kidney.

Synthesis and calcium channel antagonist activity of nifedipine analogues with methylthioimidazole substituent

Various diester analogues of nifedipine, in which the orthonitrophenyl group at position 4 is replaced by 1-methyl-2-methylthio-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists on guinea-pig ileal smooth muscle. Nifedipine was used as standard. Comparison of the activities of symmetrical esters ( 3a– e) indicate that increasing the length of alkyl chain in C3 and C5 ester substituents increases the antagonist activity and the n-propyl ester being preferred (IC 50=2.66×10 −9 M). In asymmetrical series ( 6a– g), compound 6g having ethyl and n-butyl ester at C3 and C5 positions of basic dihydropyridine structure was found to be the most active (IC 50=1.32×10 −9 M).

A Fast and Efficient Metal-Mediated Oxidation of Isoniazid and Identification of Isoniazid-NAD(H) Adducts

It is currently believed that isoniazid (INH) is oxidised inside Mycobacterium tuberculosis to generate, by covalent attachment to the nicotinamide ring of NAD(H) (beta-nicotinamide adenine dinucleotide), a strong inhibitor of InhA, an enzyme essential for mycolic acid biosynthesis. This work was carried out to characterise the InhA inhibitors (named INH-NAD(H) adducts) which are generated, in the presence of the nicotinamide coenzyme NAD+, by oxidation of INH with manganese(III) pyrophosphate, a nonenzymatic and efficient oxidant used to mimic INH activation by the catalase-peroxidase KatG inside M. tuberculosis. The oxidation process is almost complete in less than 15 minutes (in comparison to the slow activation obtained in the KatG-dependent process (2.5 hours) or in the nonenzymatic O2/Mn(II)-dependent activation (5 hours)). The alkylation of NAD+ by the postulated isonicotinoyl radical generates, in solution, a family of INH-NAD(H) adducts. Analyses with liquid chromatography/electrospray ionisation mass spectrometry (LC/ESI-MS) and experiments performed with 18O- and 2H-labelled substrates allowed us to propose two open and four hemiamidal cyclised dihydropyridine structures as the main forms present in solution; these result from the combination of the isonicotinoyl radical and the nicotinamide part of NAD+. A small amount of a secondary oxidation product was also detected. Structural data on the forms present in solution should help in the design of inhibitors of enzymes involved in the biosynthesis of mycolic acids to act as potential antituberculosis drugs.

Structure-activity relationships and molecular modeling of 3, 5-diacyl-2,4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists.

The structure-activity relationships of 6-phenyl-1,4-dihydropyridine derivatives as selective antagonists at human A3 adenosine receptors have been explored (Jiang et al. J. Med. Chem. 1997, 39, 4667-4675). In the present study, related pyridine derivatives have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. Ki values in the nanomolar range were observed for certain 3,5-diacyl-2,4-dialkyl-6-phenylpyridine derivatives in displacement of [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5'-N-methylcarbamoyladenosine) at recombinant human A3 adenosine receptors. Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A2A receptors. Structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. A 4-phenylethynyl group did not enhance A3 selectivity of pyridine derivatives, as it did for the 4-substituted dihydropyridines. At the 2- and 4-positions ethyl was favored over methyl. Also, unlike the dihydropyridines, a thioester group at the 3-position was favored over an ester for affinity at A3 adenosine receptors, and a 5-position benzyl ester decreased affinity. Small cycloalkyl groups at the 6-position of 4-phenylethynyl-1,4-dihydropyridines were favorable for high affinity at human A3 adenosine receptors, while in the pyridine series a 6-cyclopentyl group decreased affinity. 5-Ethyl 2, 4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate , 38, was highly potent at human A3 receptors, with a Ki value of 20 nM. A 4-propyl derivative, 39b, was selective and highly potent at both human and rat A3 receptors, with Ki values of 18.9 and 113 nM, respectively. A 6-(3-chlorophenyl) derivative, 44, displayed a Ki value of 7.94 nM at human A3 receptors and selectivity of 5200-fold. Molecular modeling, based on the steric and electrostatic alignment (SEAL) method, defined common pharmacophore elements for pyridine and dihydropyridine structures, e.g., the two ester groups and the 6-phenyl group. Moreover, a relationship between affinity and hydrophobicity was found for the pyridines.

The effect of oxygen free radicals on myocardial nuclear calcium transport in rat

The 1H and 13C NMR spectra of the chiral NADH models 3 and 4 were studied both in the presence or absence of Mg2+ ions. These two compounds have a chiral carboxamide part derived from (S)-phenylalaninol but contrary to 3, compound 4 has the ability to free-rotate about the C3CO bond. Careful analysis of the spectral results and comparison with some other studies recently published in the literature allowed the following assumptions: 1-the 1,4-dihydropyridine structure is planar both in the absence or presence of magnesium ions. 2-in the case of the rigid model 3, the CO is out of the plane of the dihydropyridine structure. 3-with Mg 2+ the chiral amino alcohol moiety adopts a quasi-cyclic conformation in the case of 4 but not in the case of 3. The observed enantioselectivities are explained by the mean of ternary complexes between the model, Mg2+ and the substrate.

Different potencies of dihydropyridine derivatives in blocking T-type but not L-type Ca 2+ channels in neuroblastoma-glioma hybrid cells

Evidence has accumulated that classic L-type Ca 2+ channel blockers with a dihydropyridine structure also inhibit T-type Ca 2+ channels in certain types of central and peripheral neurons and in smooth muscle cells, albeit with a lower potency. Thus beneficial therapeutic effects of dihydropyridines in cardiovascular and neurological diseases may not only be associated with L-type but also with T-type Ca 2+ channel blockade. Little is known about the exact order of potency of dihydropyridine derivatives at T-type Ca 2+ channels. Here we investigate the efficacy and potency of four therapeutically used compounds, i.e. nifedipine, nimodipine, nicardipine, niguldipine, in the neuroblastoma-glioma cell line NG108-15. For comparative purposes the Ca 2+ channel agonist Bay K 8644 was included. Ca 2+ channel currents were measured with the whole-cell voltage clamp technique. Subtype Ca 2+ channel currents were separated by clamp protocol and selective blockers. T-type Ca 2+ channel currents were inhibited with decreasing potency in the order niguldipine>nicardipine>nimodipine>nifedipine (IC 50-values 244 nM, 2.5 μM, 9.8 μM, 39 μM), whereas L-type Ca 2+ channel currents were blocked with similar potency (IC 50 for nicardipine 75 nM). Bay K 8644 increased T-type Ca 2+ channel current at nanomolar concentrations (i.e. 95±16% increase by 300 nM). T-type Ca 2+ channel block was completely reversible with exception of the block by niguldipine. Our results indicate a variability of two orders of magnitude in potency of T-type Ca 2+ channel block by the dihydropyridine derivatives investigated. It is speculated that the relation between the L- and T-type Ca 2+ channel block may determine the therapeutic profile of a dihydropyridine derivative.

Spatial Structure of Dihydropyridines and Similarity of Dihydropyridines with some Amino Acids

Semi-empirical (PM3) and ab-initio (PSGVB) calculations were carried out for 1,4-dihydropyridine (DHP) and various of its derivatives and also for related amino acids, in order to understand the conformational changes brought about by the substituents and the peptidomimetic properties of the DPH derivatives, in terms of the similarity of their spatial structure to those of related peptides. The results allow us to derive some conformational rules in terms of the nature and position of the susbtituents on the DHP ring and also to conclude that the DHP derivatives exhibit conformational similarities to the related amino acids, which explains their binding to common receptors.

Interaction of cytostatics and chemosensitizers with the dexniguldipine binding site on P-glycoprotein

The interaction of cytostatics and chemosensitizers with the dexniguldipine binding site of P-glycoprotein was investigated in photoaffinity labeling experiments. A tritiated azidoderivative of the chemosensitizer dexniguldipine with dihydropyridine structure, [ 3H]B9209-005, was used to irreversibly label P-glycoprotein. The apparent affinity of cytostatics and chemosensitizers to this binding site was estimated from labeling experiments in the presence of increasing concentrations of compounds. From the cytostatics tested, the vinca alkaloids and taxol showed the highest affinity, anthracyclins possessed moderate affinity while methotrexate, ara C and camptothecin, cytostatics not involved in P-glycoprotein-mediated multidrug resistance, were almost inactive. The chemosensitizers GF 120918, cyclosporin A and SDZ PSC-833 inhibited photoincorporation with the highest potency. Steep dose-inhibition curves were obtained with the cyclic peptides and S9788, indicating that these compounds may bind allosterically to a separate binding site. Compounds with dihydropyridine structure with or without chemosensitizing potency were also tested and some structure-activity relationships could be derived from the data. Our data show that inhibition of photoaffinity labeling by [ 3H]B9209-005 is a valuable and reliable system for measuring the interaction with and potency of chemosensitizing compounds at P-glycoprotein. Furthermore, data obtained in this test system are well suited to investigate structure-activity relationships for chemosensitizers at P-glycoprotein. In addition cytostatics underlying P-glycoprotein-mediated multidrug resistance can be identified.

Study of the mechanism of the hydride transfer with a highly reactive and stereoselective NADH model

The 1H and 13C NMR spectra of the chiral NADH models 3 and 4 were studied both in the presence or absence of Mg 2+ ions. These two compounds have a chiral carboxamide part derived from (S)-phenylalaninol but contrary to 3, compound 4 has the ability to free-rotate about the C 3CO bond. Careful analysis of the spectral results and comparison with some other studies recently published in the literature allowed the following assumptions: 1-the 1,4-dihydropyridine structure is planar both in the absence or presence of magnesium ions. 2-in the case of the rigid model 3, the CO is out of the plane of the dihydropyridine structure. 3-with Mg 2+ the chiral amino alcohol moiety adopts a quasi-cyclic conformation in the case of 4 but not in the case of 3. The observed enantioselectivities are explained by the mean of ternary complexes between the model, Mg 2+ and the substrate.

Metabolic Fate of Felodipine in Man

A new metabolic pathway for felodipine was confirmed by identification and quantification of new felodipine metabolites retaining the dihydropyridine structure. Following administration of a 10mg dose to 6 healthy subjects, felodipine was rapidly absorbed, reaching maximum plasma concentration (Cmax) [22.5 ng/ml] after 1.5 hours, and was then eliminated with a half-life of 3.1 hours. The pyridine metabolite had a similar plasma concentration-time course to that of the parent compound, with a Cmax of 30.1 ng/ml and an elimination half-life of 2.8 hours. In contrast, the dihydropyridine metabolite (5-carboxy derivative) reached a Cmax value (47.8 ng/ml) 1.9 hours after administration and was eliminated with a half-life of 8.1 hours. This plasma dihydropyridine metabolite was identified by GC-MS (GC-mass spectrometry) in comparison with the standard material. The dihydropyridine metabolite was not detectable in urine.

Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein

The (−)-isomer of verapamil is 10-fold more potent as a calcium antagonist than the (+)-isomer. However, both enantiomers are equally effective in increasing cellular accumulation of anticancer drugs [Gruber et al., Int J Cancer 41: 224–226, 1988]. In addition to verapamil, there exists a wide variety of stereoisomers with phenylalkylamines and dihydropyrdine structures which markediy differ in their potency as calcium antagonists. We have tested these drugs for their ability to increase intracellular accumulation of [ 3H]vinblastine ([ 3H]VBL) in a doxorubicin-resistant cell line (F4-6RADR) derived from the Friend mouse leukemia cell line (F4-6P) and in COS-7 monkey kidney cells. Both cell types express substantial amounts of multidrug resistance gene 1 mRNA and P-glycoprotein as revealed by RNA and immuno blot analysis. The enantiomers with phenylalkylamine structures [(±)-verapamil; (±)-devapamil; (±)-emopamil)] and with dihydropyridine structures [(±)-isradipine; (±)-nimodipine; (±)-felodipine; (±)-nitrendipine; (±)-niguldipine] increased [ 3H]VBL accumulation in both cell lines at micromolar concentrations. Although the stereoisomers of these drugs differ markedly in their potency as calcium channel blockers they were about equally effective in increasing VBL levels in the cells. There was no substantial difference in the potencies of the phenylalkylamine drugs in affecting cellular [ 3H]VBL transport. Major potency differences, however, were observed in the dihydropyridine drug series with the niguldipine isomers as the most effective drugs. Moreover, the niguldipine enantiomers were equally as effective in reversing VBL resistance in F4-6RADR cells as were the verapamil enantiomers. Since (-)-niguldipine (B859-35) displays a 45-fold lower affinity for calcium channel binding sites than (+)-niguldipine, but is equally potent in inhibiting drug transport by P-glycoprotein and in reversing drug resistance, it may be, in addition to (+)-verapamil, another usefui candidate drug for the treatment of multidrug resistance in cancer patients.

Studies on the Metabolic Fate of Felodipine. (IV). Identification of New Metabolites of Felodipine in Rat.

Two novel metabolites of felodipine were isolated from rat bile or in an in vitro system using rat liver preparations. Their chemical structures were identified by comparative analysis with authentic samples. Both metabolites were formed by ester hydrolysis of felodipine. One was a 3-carboxyl derivative and the other a 5-carboxyl derivative ; both were identified as having dihydropyridine structures and were shown to be major metabolites in rat plasma.

Pharmacokinetics and Pharmacodynamics of Nitrendipine in Healthy Subjects and Patients with Kidney and Liver Disease

Nitrendipine [3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate] is a calcium antagonist with a dihydropyridine structure that has a great structural resemblance to nifedipine. Instead of a methyl group in position 3, it has an ethyl group and the NO2 group is in the meta instead of in the ortho position. These minor structural differences have a pronounced impact with respect to both the pharmacokinetics and pharmacodynamics of nitrendipine as compared to nifedipine. Based on equimolar plasma concentrations, nitrendipine is on average three times more potent than nifedipine with regard to the reduction of peripheral vascular resistance, arterial blood pressure, and increased leg blood flow. The terminal half-life is on average 8 h, and thus substantially longer than the terminal half-life of 2-3 h for nifedipine. Despite its almost complete absorption, bioavailability is on average 15-25% and shows great interindividual variability ranging from 7 to 40%. The systemic plasma clearance of the drug is on average 18 ml/min/kg and thus approaches the liver blood flow. In patients with liver cirrhosis, the half-life is prolonged to 19.6 h, the total plasma clearance is decreased by 50%, and the bioavailability is more than doubled to 54%. No data are available if liver disease alters the pharmacodynamic response of the drug. Kidney disease has some effect on the disposition of the drug. Systemic clearance is not changed but the terminal elimination half-life is slightly prolonged to 10.5 h. This increase in half-life is due to an increased volume of distribution. Bioavailability, which is 21.2%, is not grossly altered in renal failure.

Antihypertensive Effects and Pharmacokinetics of Felodipine Combined with a β-Blocker and a Diuretic

The antihypertensive effect of felodipine, a new calcium antagonist with dihydropyridine structure, was investigated in 25 patients with essential hypertension that was not controlled on standard triple therapy (a beta-blocker, a diuretic, and a vasodilator). After substituting the previous vasodilator with felodipine, blood pressure was reduced and remained well controlled during a 2 year follow-up period. After about 1 1/2 years of treatment, felodipine was compared double-blind with placebo in a subgroup of 10 patients while keeping the same beta-blocker and diuretic therapy. Compared with the placebo, felodipine lowered blood pressure during a 12 h interval, which supports a twice-daily dosage in clinical practice. Determination of the plasma concentrations of felodipine during steady-state conditions showed a mean elimination half-life of 23.4 +/- 11.1 h. During long-term therapy, tolerance was good, and felodipine seems to be a safe and efficient antihypertensive agent in combination with a beta-blocker and a diuretic in patients whose hypertension is not adequately controlled on standard triple therapy.

Amino acid addition to 4-formylpyridine and its quaternized salt: transamination

Flow and stopped-flow 1H nuclear magnetic resonance spectroscopy of aqueous solutions have been used to study the reaction between 4-formylpyridine or 4-formyl-1-methylpyridinium iodide and D,L-alanine as well as its methyl ester and D,L-alanylglycine. Because resolved signals can be observed for the alanyl-CH3-proton resonance of the amine, the aldimine, and the ketimine, the time dependence of each species was followed, and the sequence of steps leading to transamination could be studied. As was found previously with alanine, the conversion of aldimine to ketimine appears to be too slow to be detected when 4-formylpyridine is reacted with alanine (pH range to 10) or alanyl methyl ester (pH range 7 to 8). For these systems reaction proceeds until an equilibrium between aldimine and reactants is established. Because the equilibrium constant for the addition step is measured separately, the constant for the equilibrium Kd between carbinolamine and aldimine could be determined. The rate constants for the forward and reverse steps of this equilibrium are independent of buffer but depend on pH. For alanylglycine between pH 7.2 and 7.7, the same process was found to occur. However between pH 8.2 and 10.1, the aldimine derived from this amine undergoes a prototropic shift to form the corresponding ketimine with a rate constant that depends on the concentration of DABCO at each pH. Thus, the change from α-carboxylate anion of alanine (or other amino acids studied previously) to the uncharged α-amide of alanylglycine causes a distinct increase in the rate of prototropic shift when 4-formylpyridine is the electrophile. For the more reactive 4-formyl-1-methylpyridinium iodide, aldimine to ketimine conversion was found to occur for alanine and alanylglycine. During reaction of the latter, a broad nmr signal occurs. This signal may be due to the dihydropyridine structure suggested for an intermediate detected spectrophotometrically for the reaction involving alanine or glycine.