Dihydropyridines 1 -labelled

Nakayama H, Taki M, Striessnig J, Glossmann H, Catterall WA, Kanaoka Y. (1991) Identification of 1,4-dihydropyridine binding regions within the alpha 1 subunit of skeletal muscle Ca channels by photoaffmity labeling with diazipine. Proc Natl Acad Sci USA 88 9203-9207. 

Reynolds, I.J., Snowman, A.M. and Snyder, S.H. (1986) (-)-[3H] desmethoxyverapamil labels multiple calcium channel modulator receptors in brain and skeletal muscle membranes differentiation by temperature and dihydropyridines. The Journal of Pharmacology and Experimental Therapeutics, 237, 731—738. 

As mentioned before, nifedipine was the first marketed dihydropyridine CCB. Initially, the drug indication was exclusively for angina, but the more recently developed extended release (ER) formulations are used off-label primarily for hypertension (Bayer, 2004). The extended-release tablets use a cellulose coat that extends their release time. The half-life of the ER formulation is reported as 7 h, whereas the immediate-release formulation has a half-life of 2 h (Bayer). 

Lithium aluminum hydride reacts readily with pyridine to yield lithium tetrakis-(A/-dihydropyridyI)aluminate, LiAI(NR2)4 (structures 108 and 109).152 The NR2 groups represent 1,4-dihydro- and/or, 1,2-dihydropyridyl residues. The two diverse N-ligands may be part of the same molecule in association with the A1 metal. The structure of the adduct has been investigated by IR and NMR spectroscopy and by deuterium-labeling experiments. The latter approach has been used to determine the 1,2 to 1,4 ratio, which is found to be close to 1 2 when the reaction is carried out at room temperature. The N—A1 bond is assumed to be covalent, though of a markedly more ionic character as compared to the N—H bond in dihydropyridines.152... 

The direct attack of proton from the solvent on the intermediate dihydropyridine as well as the over-all mechanism of the reduction received support from the extent and position of deuterium labeling in the product from the reduction of l-methyl-4-phenyl-pyridinium iodide (7) with sodium borohydride in dimethylformamide and deuterium oxide. The l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (9) formed was shown by nuclear magnetic resonance (NMR) and mass spectral analysis to contain approximately one deuterium atom located at the 3-position.13,14 This is the result to be expected from the pathway shown in Eq. (3) if the electrophile were a deuteron. 

The synthesis of this tritium-labelled dihydropyridine derivative, 137, a powerful antihypertensive agent attenuating smooth muscle and cardiac muscle contractions by blocking the influx of calcium ions into vascular smooth muscle cells143, has been carried out144 by preparing initially the 3-nitrobenzaldehyde[4,6-3H] 138 of high specific activity in the four steps shown in equation 58. It was then used in the Hantzsch... 

Nimodipine 288 has been labelled with nC in order to study the density of the L-type calcium channels and the dihydropyridine binding275fl,275b sites (equation 115) with the PET technique276. 

Kiue A, Sano T, Suzuki KI, Inada H, Okumura M, Kikuchi J, Sato SI, Kohno K, Kuwano M (1990) Activities of newly synthesized dihydropyridines in overcoming of vincristine resistance, calcium antagonism, and inhibition of photoaffinity labeling of P-glycoprotein in rodents. Cancer Res 50 310-317... 

Carbon-11 labelled calcium channel antagonists C-nifedipine, C-nisoldipine, C-nitrendipine and C-CFj-nifedipine possessing vasodilating and hypotensive properties have been synthesized using a modified Hantzsch-type cyclocondensation proce-dure . Condensation of aldehydes 242, 243 and 244 with 3-aminocrotonic acid esters 245, 246, 247 and with acetoacetic ester 248 produced in one pot after 12 hours reflux in dry ethanol the methyl sulphonylethyl protected dihydropyridines 249-252. Deprotection of the carboxylic acids by alkaline hydrolysis followed by conversion into the dihydropyridine monocarboxylic acids 253-256 gave potassium salts in situ, and subsequent methylation with CH3I produced the corresponding labelled title compounds 257-260 (equation 102),... 

PROBLEM 15.12 The mechanism of enzymatic oxidation has been studied by isotopic labeling with the aid of deuterated derivatives of ethanol. Specify the number of deuterium atoms that you would expect to find attached to the dihydropyridine ring of the reduced form of the nicotinamide adenine dinucleotide coenzyme following enzymatic oxidation of each of the alcohols given ... 

Betalains.—Betacyanins, e.g. betanin (187), are red-violet pigments found in plants of the Centrospermae order. Radioactive dopa [as (186)] has been found to label the dihydroindole portion of betanin to a minor extent.Most of the label appears in the dihydropyridine moiety. This moiety, in betanin (187) ... 

A variety of derivatives of 3 -azido-2, 3 -dideoxynucleosides have been prepared in order to study the mechanism of action, to improve the transport of the drug or to obtain more selective compounds. These include tritium labelled derivatives of AZT [64, 65], various derivatives of 3 -azido-3 -deoxythymidine triphosphate [66, 67] and quaternary salts and dihydropyridine derivatives of AZT [68]. 

A full paper has now appeared on the previously described thermal dimerization of the 1,6-dihydropyridine (57). The dimer (58) undergoes a further thermal rearrangement to give (59). It has been established, by the use of appropriately labelled substrates, that (59) itself is also subject to degenerate thermal rearrangement. 

The validity of (6.267) as a biosynthetic intermediate is supported by the isolation of simple secodine (6.268) derivatives from plants and by the specific incorporation of labelled secodine (6.268) into vindoline (6.244) the tritium loss from (6.268) labelled in the dihydropyridine ring on transformation into vindoline (6.244) is consistent with involvement of secodine (6.268) via a more highly oxidized intermediate [as (6.267) [187]. 

We have recently found that unsaturated ( )-ester aldehydes 1 (Scheme 1) quantitatively reacted with primary amines, including lysine, within a very short time ( 5 min) in an extremely diluted organic buffer solution (10 -10 M) to yield 1,2-dihydropyridines as irreversible products through the accelerated 6- r-azaelectrocyclization of the intermediary Schiff base [72, 73]. To the best of our knowledge, our reaction where unsaturated aldehyde 1, for instances, reacts with enzyme to modify several Lys residues within 15 min at room temperature is the fastest conjugation reaction with lysines in water (Fig. 1). We wondered if this reaction would work as a new protocol for Lys labeling. 

---