Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models.

Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids - termed oxa-iboga - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton.

Structural pharmacology and therapeutic potential of 5-methoxytryptamines.

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ).

Site selective C-H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy.

Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material "kratom", which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy.

A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats.

Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined.

Hypervalent Iodine Based Reversible Covalent Bond in Rotaxane Synthesis.

Reversible covalent bonds play a significant role in achieving the high-yielding synthesis of mechanically interlocked molecules. Still, only a handful of such bonds have been successfully employed in synthetic procedures. Herein, we introduce a novel approach for the fast and simple preparation of interlocked molecules, combining the dynamic bond character of bis(acyloxy)iodate(I) anions with macrocyclic bambusuril anion receptors.

Dynamic Interactions in Synthetic Receptors: A Guest Exchange Saturation Transfer Study.

The accumulated knowledge regarding molecular architectures is based on established, reliable, and accessible analytical tools that provide robust structural and functional information on assemblies. However, both the dynamicity and low population of noncovalently interacting moieties within studied molecular systems limit the efficiency and accuracy of traditional methods. Herein, the use of a saturation transfer-based NMR approach to study the dynamic binding characteristics of an anion to a series of synthetic receptors derived from bambusuril macrocycles is demonstrated.

Unsubstituted Bambusurils: Post-Macrocyclization Modification of Versatile Intermediates.

A new bambusuril derivative, , lacking substituents on the ureidic nitrogen atoms, has been isolated and characterized. This macrocycle was prepared by the deprotection of bambusuril . is attractive for use as a starting compound for the preparation of other bambusuril derivatives, which was demonstrated via propargylation and the copper-catalyzed click reaction performed on the macrocycle.

Supramolecular Storage and Controlled Photorelease of an Oxidizing Agent using a Bambusuril Macrocycle.

The oxidizing ability of peroxodisulfate upon complexation inside the Bambusuril macrocycle cavity is inhibited. This dianionic agent can be released on demand from its stable 1:1 complex in water (log K =6.9 m ) by addition of a more strongly bound anion, such as iodide (log K =7.

Modulation of Bambusuril Anion Affinity in Water.

Neutral and negatively charged anion receptors functioning in pure water are rare in supramolecular chemistry. Moreover, studies on adjusting the affinity of such receptors toward anions in water are absent from the literature. Two new bambusurils, 1 a and 2 a, were prepared to demonstrate that the affinity of bambusurils towards anions can be altered by the length of carboxyalkyl groups attached to the macrocycles.

Anion Binding Inside a Bambus[6]uril Macrocycle in Chloroform.

Bambus[6]urils are a class of neutral anion receptors with outstanding binding properties in various solvents. The host-guest associations of bambusurils in aqueous environments have been investigated in detail, but their behavior in nonpolar solvents has not yet been reported. This paper presents isothermal calorimetry and H NMR data on the binding of dodecabenzylbambus[6]uril (Bn BU[6]) to seventeen anions in chloroform.

Anion Binding Inside a Bambus[6]uril Macrocycle in Chloroform.

Invited for this month's cover is the group of Prof. Vladimir Sindelar from Masaryk University, Czech Republic. The cover picture shows the bambusuril macrocycle which binds various inorganic anions in the center of its cavity with high affinity and selectivity in chloroform.

Counterion influence on the N-I-N halogen bond.

A detailed investigation of the influence of counterions on the [N-I-N] halogen bond in solution, in the solid state and is presented. Translational diffusion coefficients indicate close attachment of counterions to the cationic, three-center halogen bond in dichloromethane solution. Isotopic perturbation of equilibrium NMR studies performed on isotopologue mixtures of regioselectively deuterated and nondeuterated analogues of the model system showed that the counterion is incapable of altering the symmetry of the [N-I-N] halogen bond.

Real-time analysis of multiple anion mixtures in aqueous media using a single receptor.

Bambusuril-based receptors have been used in conjunction with (1)H NMR spectroscopy to recognize mixtures of inorganic anions in aqueous solutions. This was achieved by examining complexation-induced changes in the receptors' (1)H NMR fingerprints. This approach enables the simultaneous identification of up to 9 anions and the quantification of up to 5 anions using a single receptor in DMSO-d6 containing 5% D2O.

A bambusuril macrocycle that binds anions in water with high affinity and selectivity.

Synthetic receptors that function in water are important for the qualitative and quantitative detection of anions, which may act as pollutants in the environment or play important roles in biological processes. Neutral receptors are particularly appealing because they are often more selective than positively charged receptors; however, their affinity towards anions in pure water is only in range of 1-10(3)  L mol(-1) . The anion-templated synthesis of a water-soluble bambusuril derivative is shown to be an outstanding receptor for various inorganic anions in pure water, with association constants of up to 10(7)  L mol(-1) .

Water-mediated inclusion of benzoates and tosylates inside the bambusuril macrocycle.

A supramolecular complex between benzoates and a bambusuril crystallizes out immediately after mixing in chloroform but only in the presence of residual water molecules. In this complex each of the two portals of the macrocycle is occupied by one benzoate. Carboxylate groups are connected through hydrogen bonding interactions with one molecule of water positioned between them in the center of the bambusuril cavity.

Bambus[n]urils: a new family of macrocyclic anion receptors.

A recently discovered anion receptor is jointed by three related macrocycles differing in the number of glycoluril units and type of substitution. The synthesis is carried out in nonpolar solvents compared to aqueous media used in the case of the original macrocycle. The size of macrocycle is controlled by a template.