Dihydropyridines selectivity

Ferry, D.R., Russell, M.A., and Cullen, M.H. (1992) P-glycoprotein possesses a 1,4-dihydropyridine-selective drug acceptor site which is alloserically coupled to a vinca-alkaloid-selective binding site. Biochem Biophys Res Commun, 188, 110-445. 

A Hantzsch 1,4-dihydropyridine selectively reduced the exocyclic double bond of 4-arylmethylene- and 4-alkylidene-4Ef-isoxazol-5-ones with high efficiency to give 2H-isoxazol-5-ones <05SL1579>. 

Establishing a specific pharmacological profile for the MTX-induced Ca entry is difficult, since this toxin seems to activate more than one cation channel depending on the cell type. As already indicated, MTX can apparently activate voltage dependent and voltage independent Ca channels depending on the cell type. For example, Freedman et al. [32] showed that in neuroblastoma-glioma hybrid cells the MTX-induced Ca increase was at least partially blocked by dihydropyridines selective for L-type Ca channels at low concentrations (10 -10 M). In contrast, the... 

Even more highly selective ketone reductions are earned out with baker s yeast [61, 62] (equations 50 and 51) Chiral dihydronicotinamides give carbonyl reductions of high enantioselectivity [63] (equation 52), and a crown ether containing a chiral 1,4-dihydropyridine moiety is also effective [64] (equation 52). 

An obvious outcome of the Hantzsch synthesis is the symmetrical nature of the dihydropyridines produced. A double protection strategy has been developed to address this issue. The protected chalcone 103 was reacted with an orthogonally protected ketoester to generate dihydropyridine 104. Selective deprotection of the ester at C3 could be accomplished and the resultant acid coupled with the appropriate amine. Iteration of this sequence with the C5 ester substituent ultimately gave rise to the unsymmetrical 1,4-dihydropyridine 105. 

Marazano and co-workers have also applied the reactions of tryptamine with various Zincke salts, including 115 (Scheme 8.4.39), in the synthesis of pyridinium salts such as 116. This type of product is useful for further conversion to dihydropyridine or 2-pyridone derivatives. For example, in a different study, Zincke-derived chiral pyridinium salts could be oxidized site-selectively with potassium ferricyanide under basic conditions as a means of chiral 2-pyridone synthesis (117 —> 118, Scheme 8.4.40). 

Similarly, the regiospecific 1,3-dipolar cycloaddition reaction of 1-methyl-1,2-dihydropyridines 41 with cyanogen azide (50a) and selected organic azides 50c and 50g afforded 2-methyl-2,7-diazabicyclo[4.1.0]hept-4-enes 57, which can be elaborated to 1-methyl-l,2,5,6-tetrahydropyridylidene-2-cyanamide (58) and 1-methyl-2-piperidylidenes 59a-d (85CJC2362). 

A similar phenomenology attends the actions of maitotoxin, another large organic molecule that induces a Ca selective membrane permeability (see chapter by Ohizumi Kobayashi in this volume). None of the known inhibitors of Ca channels, including Co , Cd, dihydropyridines, and verapamil or diltiazem affect the maitotoxin-induced increase in Ca permeability. To date, an association between maitotoxin and an existing Ca pump or exchange protein has not been demonstrated. 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

Calcium antagonists are able to affect nitric oxide production and suppress the peroxyni-trite-induced damage. Thus, nifedipine enhanced the bioavailability of endothelial NO in porcine endothelial cell cultures supposedly through an antioxidative mechanism [288], Pretreatment with nisoldipine, a vascular-selective calcium blocker of dihydropyridine-type, of confluent bovine aortic endothelial cells suppressed the peroxynitrite-induced GSH loss and increased cell survival [289]. 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

Hamaguchi, N., True, T.A., Saussy, D.L., Jr and Jeffs, P.W. (1996) Phenylalanine in the second membrane-spanning domain of alpha lA-adrenergic receptor determines subtype selectivity of dihydropyridine antagonists. 

The electroreduction of deactivated pyridines or pyridinium salts affords selectively the corresponding 1,2- or 1,4-dihydropyridine derivatives according to the position of the substituents (Schemes 133 and 134) [243]. In the same experimental conditions a monoactivated pyridine is not reducible. 

Dihydropyridine-CA have been developed with a certain degree of vascular selectivity, which implies that at therapeutic doses such compounds would have less negative influence on cardiac contractile force or none at all. Indeed, a few of such compounds are devoid of cardiodepressant (negative inotropic) activity. Examples of such compounds are amlodipine, felodipine, isradip-ine, lacidipine, lercanidipine and manidipine. 

The clinically available calcium chaimel antagonists have also proved to be invaluable as molecular probes with which to identify, isolate, and characterize calcium channels of the voltage-gated family. In particular, the 1,4-dihydropyridines with their high affinity, agonist-antagonist properties, and selectivity have become defined as molecular markers for the L-type chaimel. 

Synthetic drugs of comparable selectivity and affinity to the 1,4-dihydropyridines do not yet exist for the other channel types, T, N, P/Q, and R these remain characterized by complex polypeptide toxins of the aga- and conotoxin classes. Neuronal pharmacology, including that of the central nervous system (CNS), is dominated by the N, P/Q, and R channels. This underscores the normally weak effect of L-channel antagonists on CNS function. Drugs that act at the N, P, and R channels with comparable selectivity and affinity to the 1,4-dihydropyridines may be expected to offer major potential for a variety of CNS disorders, including neuronal damage and death from ischemic insults. 

B. The other three drugs (dihydropyridines) are characterized by relatively selective vasodilator effects with little if any cardiac effects at doses employed clinically for hypertension or angina. 

This case report (Figures 6-4Ato 6-4C) (McDermut et al. 1995) of selective response to dihydropyridine CCBs but not a phenylalkylamine CCB is of considerable interest in relationship to the patient s history of nonre-sponsivity to multiple tricyclic antidepressants, the selective serotonin reuptake inhibitors, lithium, carbamazepine (the patient developed drug-induced hepatitis on carbamazepine and was unable to be evaluated), alprazolam, trazodone, and phenelzine. This suggests that patients with refractory mood disorders may have differential responses to various CCBs and that nonresponse to one CCB does not preclude response to another CCB, particularly if the other CCB is from a different category (Table 6-3). 

The increase of intraneuronal calcium is related to degeneration and cellular death. Excitatory amino acids have been associated with calcium levels. In this sense, the blocking agents of the inflow of calcium to the neurons, which also produce a vasodilation, could have a therapeutic use in AD. Nimodipine, a dihydropyridine with a selective action on the vascular brain territory, has shown improvement in some psychometric batteries of patients with AD at 90-180 mg/day [Jarvik 1991]. However, more studies with this drug are needed. 

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