Claudio Martínez

The endocannabinoid (eCB) system regulates several brain functions and is implicated in neurological disorders. The pharmacological blockade of cannabinoid receptors has a therapeutic potential for various cognitive deficits, but also produces severe psychiatric side effects. Hence, new cannabinoid compounds that potentiate therapeutic effects, while minimizing toxicity, are required. In this study, we synthesized and characterized a novel antagonist/inverse agonist of CB ₁ receptors. UVI3502 showed affinity for two [ ³ H]CP55,940 binding sites (IC _50Hi 0.47 ± 1.94 nM and IC _50Lo 1470 ± 1.80 nM). Subsequent binding assays performed in CB ₁ and CB ₂ overexpressing membranes determined that the low affinity binding site corresponded to CB ₁ , but the high-affinity binding site of UVI3502 did not correspond to CB ₂ and the possibility of it corresponding to GPR55 was analyzed. The affinity of UVI3502 for CB ₁ receptors was further confirmed with neuroanatomical specificity by autoradiography in key brain areas, in which functional [ ³⁵ S]GTPɣS assays demonstrated that UVI3502 behaved as an antagonist/inverse agonist of CB ₁ receptors, blocking the stimulation evoked by potent cannabinoid receptor agonist CP55,940 and decreasing basal [ ³⁵ S]GTPɣS binding. The in silico characterization of the binding to CB ₁ receptor through molecular docking and molecular dynamics suggests that this activity is explained by the planar and rigid structure of UVI3502, which is optimal for interactions with the inactive state of the receptor. These results indicate that UVI3502 is a novel antagonist/inverse agonist of CB ₁ receptors, making it a compelling candidate for pharmacologically blocking cannabinoid receptors in the central nervous system. Significance Statement: UVI3502 is a novel antagonist/inverse agonist of CB ₁ receptors, with almost no affinity for CB ₂ receptors and an additional high-affinity binding site for a third, cannabinoid-like receptor, potentially GPR55. In relevant brain areas for learning and memory processes with a high expression of CB ₁ , UVI3502 blocks the stimulation evoked by the cannabinoid receptor agonist CP55,940, rendering it as an interesting compound for the pharmacological blockade of cannabinoid receptors in the central nervous system.

A photochemical catalytic amination of arenes is presented. The reaction proceeds under benign iodine catalysis in the presence of visible light as the initiator and provides access to a range of differently substituted arylamines. A total of 29 examples demonstrate the broad applicability of this mild oxidation method. The scope of the reaction could further be expanded to silyl‐tethered derivatives, which undergo intramolecular amination upon formation of seven‐membered heterocycles. Cleavage of the silicon tether provides access to the corresponding 3‐substituted anilines.

A computational study of the mechanism for the iodine(III)‐mediated oxidative amination of alkenes explains the experimentally observed substrate dependence on product distribution. Calculations with the M06 functional have been carried out on the reaction between PhI(N(SO₂Me)₂)₂ and three different representative substrates: styrene, α‐methylstyrene, and (E)‐methylstilbene. All reactions start with electrophilic attack by a cationic PhI(N(SO₂Me)₂)⁺ unit on the double bond, and formation of an intermediate with a single C−I bond and a planar sp² carbocationic center. The major path, leading to 1,2‐diamination, proceeds through a mechanism in which the bissulfonimide initially adds to the alkene through an oxygen atom of one sulfonyl group. This behavior is now corroborated by experimental evidence. An alternative path, leading to an allylic amination product, takes place through deprotonation at an allylic C−H position in the common intermediate. The regioselectivity of this amination depends on the availability of the resonant structures of an alternate carbocationic intermediate. Only in cases where a high electronic delocalization is possible, as in (E)‐methylstilbene, does the allylic amination occur without migration of the double bond.

New palladium(II)–phthalimidato complexes have been synthesized, isolated, and structurally characterized. As demonstrated from over 30 examples, they constitute superior catalysts for oxidative amination reactions of alkenes with phthalimide as the nitrogen source. This work streamlines vicinal difunctionalization of alkenes and provides access to significantly improved and experimentally simplified synthetic protocols.

Iodine reagents have been identified as economically and ecologically benign alternatives to transition metals, although their application as molecular catalysts in challenging CH oxidation reactions has remained elusive. An attractive iodine oxidation catalysis is now shown to promote the convenient conversion of carbon–hydrogen bonds into carbon–nitrogen bonds with unprecedented complete selectivity. The reaction proceeds by two interlocked catalytic cycles comprising a radical chain reaction, which is initiated by visible light as energy source. This unorthodox synthetic strategy for the direct oxidative amination of alkyl groups has no biosynthetic precedence and provides an efficient and straightforward access to a general class of saturated nitrogenated heterocycles.

Retinoid receptors (RARs and RXRs) transduce the signals of their natural and synthetic ligands (retinoids and rexinoids) to cellular transcriptional machinery to induce gene programs that control diverse biological and physiological effects on organisms. All‐trans‐retinoic acid, the natural ligand for RARs, is used therapeutically for the treatment of acute promyelocytic leukemia (APL), whereas the synthetic rexinoid bexarotene (a representative member of the aromatic retinoids or arotinoids) is approved for the treatment of cutaneous T‐cell lymphoma (CTCL). Other retinoids have found applications in the topical treatment of skin disorders. In continuation of previous work on the naphthalene‐based arotinoid scaffold, we synthesized a new series of (3‐halo)benzoic acids connected to C5‐ or C8‐substituted naphthyl rings via (E)‐ethenyl and amide and, for the C5 series, (E)‐chalcone linkers. These compounds were evaluated as RAR modulators in comparison with previously described dihydronaphthalene arotinoids with the same substitution pattern. Transactivation studies in this series revealed an absence of synergy between small halogen atoms (F, Cl) at C3 and the groups at C5 or C8, as had been observed on some of the dihydronaphthalene analogues. Instead, non‐halogenated 4‐(2‐naphthamido)benzoic acid derivatives transactivated toward the RARβ subtype in preference to the paralogues. The derivatives with bulkier substituents at C8 were characterized as dual RARβ/RARα antagonists, and (E)‐4‐[(8‐(phenylethynyl)naphthalene‐2‐yl)ethenyl]benzoic acid (11 c), with an ethenyl connector, was shown to be a potent antagonist of RARα.

Arotinoids containing a C5,C8-diphenylnaphthalene-2-yl ring linked to a (C3-halogenated) benzoic acid via an ethenyl connector (but not the corresponding naphthamides), which are prepared by Horner–Wadsworth–Emmons reaction of naphthaldehydes and benzylphosphonates, display the rather unusual property of being RXR agonists (15-fold induction of the RXR reporter cell line was achieved at 3- to 10-fold lower concentration than 9-cis-retinoic acid) and RAR antagonists as shown by transient transactivation studies. The binding of such bulky ligands suggests that the RXR ligand-binding domain is endowed with some degree of structural elasticity.

New reaction conditions for the rapid and productive intermolecular aminochlorination reaction of alkenes using a combination of chloramine‐T and a Brønstedt acid are described. Upon simple protonation of chloramine‐T, conditions for a mild and selective aminochlorination are obtained. In addition, the reaction can proceed to form either of the two possible regioisomers, depending on whether a stoichiometric amount of such an acid activator or acetic acid is used as solvent. The reaction is operative for all different classes of alkenes. A total of over 50 examples is presented to illustrate this concept. magnified image