Citrus limonoids (CLs) are a group of highly oxygenated terpenoid secondary metabolites found mostly in the seeds, fruits and peel tissues of citrus fruits such as lemons, limes, oranges, pumellos, grapefruits, bergamots, and mandarins. Represented by limonin, the aglycones and glycosides of CLs have shown to display numerous pharmacological activities including anticancer, antimicrobial, antioxidant, antidiabetic and insecticidal among others. In this review, the chemistry and pharmacology of CLs are systematically scrutinised through the use of medicinal chemistry tools and structure-activity relationship approach. Synthetic derivatives and other structurally-related limonoids from other sources are include in the analysis. With the focus on literature in the past decade, the chemical classification of CLs, their physico-chemical properties as drugs, their biosynthesis and enzymatic modifications, possible ways of enhancing their biological activities through structural modifications, their ligand efficiency metrics and systematic graphical radar plot analysis to assess their developability as drugs are among those discussed in detail.

To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthesized chiral analogs of mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by vaseline-gap voltage clamp method. The effect of each drug on the maximal peak Na+ transient (I(Na) max) was evaluated as both tonic and use-dependent block by using infrequent depolarizing stimulation and trains of pulses at 2-10 Hz frequency, respectively. The mexiletine analog 3-(2,6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent than mexiletine in producing a tonic block but produced a remarkable use-dependent block. In fact, the half-maximal concentration (IC50) for tonic block of S(-)-Me2 was 108 microM vs. 54.5 microM of R(-)-mexiletine, but the IC50 was 6.2 times lowered by the 10 Hz stimulation with respect to the 2.4 fold decrease observed with mexiletine. The R(-)-mexiletine and the S(-)-Me2 were about twofold more potent than the corresponding enantiomers in producing a tonic block, but the stereoselectivity attenuated during use-dependent blockade. The more lipophilic 2-(4-chloro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as raceme, produced a potent and irreversible tonic block of the sodium currents with an IC50 of 29 microM, but had a less pronounced use-dependent inhibition, with a 1.9 fold decrease of the IC50 at 10 Hz. The R(-) isomer of 2',6'-valinoxylidide (To1), a tocainide derivative with an increased hindrance on the chiral carbon atom, was twofold (IC50 = 209 microM) and tenfold (IC50 = 27.4 microM) more potent than R(-)-tocainide in tonic and use-dependent block, respectively. Tocainide was almost devoid of stereoselectivity, whereas the eudismic ratio of To1 [(IC50 S(+)-To1/IC50 R(-)-To1] was 1.7. As for mexiletine and Me2, the stereoselectivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 microM, and 1 min stimulation at 10 Hz was needed to show up a 50% block of I(Na) max. All the compounds produced a left-shift of the steady-state inactivation curve correlated positively with the extent of use-dependent inhibition, with the exception of the cyclic To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and To1 might be promising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomitantly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skeletal muscle sodium channels.

Ligand efficiency metrics are almost universally accepted as a valuable indicator of compound quality and an aid to reduce attrition. Areas covered: In this review, the authors describe ligand efficiency metrics giving a balanced overview on their merits and points of weakness in order to enable the readers to gain an informed opinion. Relevant theoretical breakthroughs and drug-like properties are also illustrated. Several recent exemplary case studies are discussed in order to illustrate the main fields of application of ligand efficiency metrics. Expert opinion: As a medicinal chemist guide, ligand efficiency metrics perform in a context- and chemotype-dependent manner; thus, they should not be used as a magic box. Since the 'big bang' of efficiency metrics occurred more or less ten years ago and the average time to develop a new drug is over the same period, the next few years will give a clearer outlook on the increased rate of success, if any, gained by means of these new intriguing tools.

Thalidomide is a drug with interesting therapeutic properties but also with severe side effects which require a careful and monitored use. Potential immunomodulatory, antiinflammatory, anti-angiogenic and sedative properties make thalidomide a good candidate for the treatment of several diseases such as multiple myeloma. Through an increase in the degradation of TNFα-mRNA, thalidomide reduces the production of TNFα by monocytes and macrophages stimulated by lipopolysaccharide or by T lymphocytes induced by mitogenic stimuli. The decreased level of TNFα alters the mechanisms of intracellular transduction by preventing the activation of NF-kB and by decreasing the synthesis of proteins, in particular IL-6, involved in cell proliferation, inflammation, angiogenesis and protection from apoptosis. Furthermore, thalidomide affects VEGF levels by down-regulating its expression. Nowadays, new safer and less toxic drugs, analogs of thalidomide, are emerging as beneficial for a more targeted treatment of multiple myeloma and several other diseases such as Crohn';s disease, rheumatoid arthritis, sarcoidosis, erythema nodosum leprosum, graft-versus-host disease.

The effects of the enantiomers of mexiletine were tested on sodium currents of frog skeletal muscle fibers recorded by means of the three vaseline gap voltage clamp method and compared with the effects produced by tocainide enantiomers. The R-(-) mexiletine produced a tonic block of the sodium current, elicited by single depolarizing test pulses from the holding potential of -100 mV to -20 mV, with an IC50 of 43.9 +/- 1 microM, whereas the corresponding S-(+) enantiomer produced the same effects at about twofold higher concentrations. A similar steroselectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-(-) and S-(+) enantiomers of mexiletine and tocainide produced a further use-dependent block of sodium currents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behavior led to a significant lowering of the IC50 values with respect to the tonic block but the eudismic ratios ([IC50S-(+)]/[IC50R(-)]) and the relative potency between mexiletine and tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h infinity), suggesting a high-affinity interaction with the inactivated sodium channels. Again a stronger potency of R-(-) vs. S-(+) enantiomers and of mexiletine vs. tocainide was observed. The excitability characteristics recorded from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to block sodium current. Thus a concentration-related increase in the threshold current required to elicit an action potential as observed along with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membrane. Again the R-(-) isomers were more potent than the S-(+) ones and mexiletine was more effective than tocainide. These data corroborate the presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enantiomers during both tonic and use-dependent block suggest that the increase in the apparent affinity of the receptor during state-dependent conformational changes of the channel does not enhance its stereospecificity. The decrease in effective concentration upon high frequency stimulation supports the potential usefulness of low doses of R-(-) mexiletine in the treatment of the abnormal hyperexcitability of the myotonic muscles, with a likely reduction of unwanted side effects.