Nicotinic Acetylcholine Receptor Agonists: A Milestone for Modern Crop Protection

The destruction of crops by invertebrate pests is a major threat against a background of a continuously rising demand in food supply for a growing world population. Therefore, efficient crop protection measures in a vast range of agricultural settings are of utmost importance to guarantee sustainable yields. The discovery of synthetic agonists selectively addressing the nicotinic acetylcholine receptors (nAChRs), located in the central nervous system of insects, for use as insecticides was a major milestone in applied crop protection research. These compounds, as a result of their high target specificity and versatility in application methods, opened a new innovative era in the control of some of the world′s most devastating insect pests. These insecticides also contributed massively to extending our knowledge of the biochemistry of insect nicotinic acetylcholine receptors. The global economic success of synthetic nAChR agonists as insecticides renders the nicotinic acetylcholine receptor still one of the most attractive target sites for exploration in insecticide discovery.     

Frameworks Tuned by Different Anions via Charge‐Assisted Weak Hydrogen Bonds

Reactions of Co(ClO₄)₂·6H₂O, Cu(NO₃)₂·3H₂O with 4,4′‐dipyridylsulfide (dps) give rise to coordination polymers {[Co(dps)₂(DMF)₂]·2(ClO₄)·2dps}_n ( 1 ) and {[Cu(dps)₂(DMF)(H₂O)]·(PF₆)·(NO₃)}_n ( 2 ) (DMF = formydimethylamine), respectively. X‐ray diffraction analyses reveal that compound 1 has a one dimensional (1D) chain structure, whereas compound 2 is built of the non‐interpenetrating wave‐like (4, 4) nets. Close inspection of the abundant charge‐assisted weak hydrogen bonds (C‐H···X, X = O, F) between the anions and frameworks in these compounds reveals that the appearance of anion may have a subtle effect on the framework topology. Furthermore, quite few examples of framework holding two different anions only via weak effects as 2 were observed in coordination polymers.     

Theoretical study of dopamine. Application of the HSAB principle to the study of drug–receptor interactions

We present a theoretical conformational study of neutral and N-protonated form of dopamine in which we relate its pharmacological activity to the chemical hardness. We have found that the neutral form presents small fluctuations in the energy and the chemical hardness with the conformational variables, whereas the N-protonated form shows significant changes in both properties. An important result is that the Principle of Maximum Hardness is satisfied. The trans coplanar rotamers are postulated as the pharmacophoric conformation(s) because these rotamers show minimal chemical hardness. In addition, we have calculated the hardness of a model of the anionic binding site of the dopamine receptor, which is formed by a formate ion and two benzenes. We have compared the hardness calculated for this model with the hardness of the isolated formate anion, and found that the hardness of the base in the binding site is lower than that of the isolated formate group. Also, it is found that the hardness of the anionic binding site model is similar to that of both trans coplanar rotamers of protonated dopamine, in agreement with the Hard and Soft Acid and Base Principle.     

Exploring anionic emission of 2-benzoyl benzimidazole in micellar environments

In this paper, an interesting transformation of the emission of anionic conformer of 2-benzoyl bezimidazole in ionic and non-ionic micelles is reported. Deprotonation is hindered in cationic and non-ionic micelles owing to probe molecule's passage deep inside positive ion-rich Stern-layer in contrast with anionic micelle. The orientation of probe molecule in the two ionic micelles, as determined from the spectral properties is opposite in nature. Micellar environment shields the formation of mono- and di-cationic species at very low pH. Three decay times of the probe in different time domains were attributed to three possible anionic species and they are modified differently in ionic and neutral micelles. Quantum chemical calculations also predict the existence of three different possible anionic species.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF A NEW FROG SKIN PEPTIDE, RANAMARGARIN

A new frog skin peptide, ranamargarin depicted as H-Asp-Asp-Ala-Ser-Asp-Arg-Ala-Lys-Lys-Phe-Tyr-Gly-Leu-Met-NH_(2′), was synthesized by the conventionalmethod. Comparisons of chemical and biological properties of both the synthetic and natural ranamargarins indicated that they were identical, so the chemical structure of ranamargarin was confirmed. Preliminary pharmacological study showed that ranamargarin was highly selective towards the SP-P subtype receptor.     

Synthesis of the selective antimuscarinic agent 4-{[cyclohexylhydroxy(2-methoxyphenyl)silyl]-methyl}-1,1-dimethylpiperazinium methyl sulfate (o-methoxy-sila-hexocyclium methyl sulfate)

The synthesis of the potent and highly selective silicon-containing antimuscarinic agent o-methoxysila-hexocyclium methyl sulfate and its corresponding tertiary amine (isolated as the dihydrochloride) is described. The quarternary compound is an o-methoxy derivative of sila-hexocyclium methyl sulfate, which represents one of the tools currently used in experimental pharmacology for the subclassification of muscarinic receptors. The o-methoxy derivative, the pharmacological profile of which differs substantially from that of the nonmethoxy compound, is also recommended as a tool for the investigation of muscarinic receptor heterogeneity.     

Translational medicine of the glutamate AMPA receptor

Psychiatric and neurological disorders severely hamper patient’s quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has only made slow progress. This is due to limited evidence on the biological basis of these disorders in humans. Synapses are essential structural units of neurotransmission, and neuropsychiatric disorders are considered as “synapse diseases”. Thus, a translational approach with synaptic physiology is crucial to tackle these disorders. Among a variety of synapses, excitatory glutamatergic synapses play central roles in neuronal functions. The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a principal component of glutamatergic neurotransmission; therefore, it is considered to be a promising translational target. Here, we review the limitations of current diagnostics and therapeutics of neuropsychiatric disorders and advocate the urgent need for the promotion of translational medicine based on the synaptic physiology of AMPAR. Furthermore, we introduce our recent translational approach to these disorders by targeting at AMPARs.     

Voltammetric Anion Sensors based on Redox‐active Ferrocene‐bearing Macrocyclic Amides

Reactions between 5‐ferrocenylisophthalic dichloride and 1,2‐bis(o‐aminophenoxy)ethane yield 1:1‐ and 2:2‐cyclization products with amide linkages, which are marked as L1 and L2 , respectively. The crystal structure of the 2:2‐macrocycle L2 is determined by X‐ray single crystal structure analysis. Interestingly, L2 affords a folded conformation due to the intermolecular π–π interaction between two isophthaloyl groups, so as to stabilize the marcocylic conformation. The electrochemical anion sensing studies of L1 and L2 show that they have a good ability to recognize H₂PO₄^–, and the 2:2‐cyclization products ( L2 ) with two ferrocene groups, more anion binding sites, and larger cavities, give better electrochemical anion recognition results than L1 .