1,4-Dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (part 2): action in other targets and antitargets.

1,4-Dihydropyridines were introduced in the last century for the treatment of coronary diseases. Then medicinal chemists decorated the 1,4-DHP nucleus, the most studied scaffold among L-type calcium channel blockers, achieving diverse activities at several receptors, channels and enzymes. We already described (Ioan et al. Curr. Med. Chem. 2011, 18, 4901-4922) the effects of 1,4-DHPs at ion channels and G-protein coupled receptors. In this paper we continue the analysis of the wide range of biological effects exerted by compounds belonging to this chemical class. In particular, focus is given to the ability of 1,4-DHPs to revert multi drug resistance that, after over 20 years of research, continues to be of great interest. We also describe activities on other targets and the action of 1,4-DHPs against several diseases. Finally, we report and review the interaction of 1,4-DHPs with the hERG channel, transporters and phase I metabolizing enzymes. This work is a starting point for further exploration of the 1,4-DHP core activities on targets, off-targets and antitargets.

1,4-Dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (part 1): action in ion channels and GPCRs.

Since the pioneering studies of Fleckenstein and co-workers, L-Type Calcium Channel (LTCC) blockers have attracted large interest due to their effectiveness in treating several cardiovascular diseases. Medicinal chemists achieved high potency and tissue selectivity by decorating the 1-4-DHP nucleus, the most studied scaffold among LTCC blockers. Nowadays it is clear that the 1,4-DHP nucleus is a privileged scaffold since, when appropriately substituted, it can selectively modulate diverse receptors, channels and enzymes. Therefore, the 1,4-DHP scaffold could be used to treat various diseases by a single-ligand multi-target approach. In this review, we describe the structure-activity relationships of 1,4-DHPs at ion channels, G-protein coupled receptors, and outline the potential for future therapeutic applications.

The flavonoid scaffold as a template for the design of modulators of the vascular Ca(v) 1.2 channels.

BACKGROUND AND PURPOSE: Previous studies have pointed to the plant flavonoids myricetin and quercetin as two structurally related stimulators of vascular Ca(v) 1.2 channel current (I(Ca1.2) ). Here we have tested the proposition that the flavonoid structure confers the ability to modulate Ca(v) 1.2 channels. EXPERIMENTAL APPROACH: Twenty-four flavonoids were analysed for their effects on I(Ca1.2) in rat tail artery myocytes, using the whole-cell patch-clamp method. KEY RESULTS: Most of the flavonoids stimulated or inhibited I(Ca1.2) in a concentration- and voltage-dependent manner with EC(50) values ranging between 4.4 µM (kaempferol) and 16.0 µM (myricetin) for the stimulators and IC(50) values between 13.4 µM (galangin) and 100 µM [(±)-naringenin] for the inhibitors. Key structural requirements for I(Ca1.2) stimulatory activity were the double bond between C2 and C3 and the hydroxylation pattern on the flavonoid scaffold, the latter also determining the molecular charge, as shown by molecular modelling techniques. Absence of OH groups in the B ring was key in I(Ca1.2) inhibition. The functional interaction between quercetin and either the stimulator myricetin or the antagonists resokaempferol, crysin, genistein, and 5,7,2'-trihydroxyflavone revealed that quercetin expressed the highest apparent affinity, in the low µM range, for Ca(v) 1.2 channels. Neither protein tyrosine kinase nor protein kinase Cα were involved in quercetin-induced stimulation of I(Ca1.2). CONCLUSIONS AND IMPLICATIONS: Quercetin-like plant flavonoids were active on vascular Ca(v)1.2 channels. Thus, the flavonoid scaffold may be a template for the design of novel modulators of vascular smooth muscle Ca(v)1.2 channels, valuable for the treatment of hypertension and stroke.

Homodimeric enzymes as drug targets.

Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homo- and/or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulating protein function therapeutically. The large number of oligomeric structures in the Protein Data Bank (http://www.rcsb.org/) reflects growing interest in proteins that function as multimeric complexes. In this review, we consider the particular case of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionally obligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservation in active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Two main types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved in protein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitors of HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitors requires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo or after unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibition through interference in dimer stability. Several techniques for studying these complex phenomena will be presented.

Ligands of diltiazem binding site: an overview of some chemotypes.

The diltiazem binding site of L-type calcium channels is the least characterized to date. In this paper, we present some of the available chemotypes that bind to the benzothiazepine binding site: natural compounds, compounds synthesized by varying the benzothiazepine scaffold, and compounds discovered by means of computational approaches.