Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice.

4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure-activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using in vitro and in vivo methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT2A and the serotonin 1A receptor (5-HT1A). The same compounds displayed affinity for 5-HT2A and 5-HT1A in mouse brain tissue in vitro and exhibited agonist efficacy in assays examining 5-HT2A-mediated calcium mobilization and ß-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT2A antagonist pretreatment, supporting 5-HT2A involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT1A antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.

A New Chemotype of Chemically Tractable Nonsteroidal Estrogens Based on a Thieno[2,3-d]pyrimidine Core.

Despite continued interest in the development of nonsteroidal estrogens and antiestrogens, there are only a few chemotypes of estrogen receptor ligands. Using targeted screening in a ligand sensing assay, we identified a phenolic thieno[2,3-d]pyrimidine with affinity for estrogen receptor α. An efficient three-step synthesis of the heterocyclic core and structure-guided optimization of the substituents resulted in a series of potent nonsteroidal estrogens. The chemical tractability of the thieno[2,3-d]pyrimidine chemotype will support the design of new estrogen receptor ligands as therapeutic hormones and antihormones.

'Foxtrot' fumarate: a water-soluble salt of N,N-di-allyl-5-methoxytryptamine (5-MeO-DALT).

The title compound, bis-(N,N-diallyl-5-meth-oxy-tryptammonium) (5-MeO-DALT) fumarate (systematic name: bis-{N-[2-(5-meth-oxy-1H-indol-3-yl)eth-yl]- N-(prop-2-en-1-yl)prop-2-en-1-aminium} (E)-but-2-enedioate), 2C17H23N2O+·C4H2O4 2-, has a single tryptammonium cation and half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by a series of N-H⋯O hydrogen bonds. These chains are combinations of R 4 4(22) rings, and C 2 2(14) and C 4 4(28) parallel chains along [111].

Influence of dityrosine nanotubes on the expression of dopamine and differentiation in neural cells.

In this study, we report the synthesis of self-assembled dityrosine nanotubes as a biologically functional scaffold and their interactions with neural cells. Quantum chemical methods were used to determine the forces involved in the self-assembly process. The physicochemical properties of the nanostructures relevant to their potential as bioactive scaffolds were characterized. The morphology, secondary structure, crystallinity, mechanical properties, and thermal characteristics of YY nanotubes were analyzed. The influence of these nanotubes as scaffolds for neural cells was studied in vitro to understand their effects on cell proliferation, morphology, and gene expression. The scanning electron microscopy and fluorescence confocal microscopy demonstrated the feasibility of nanotube scaffolds for enhanced adhesion to rat and human neural cells (PC12 and SH-SY5Y). Preliminary ELISA and qPCR analyses demonstrate the upregulation of dopamine synthesis and genes involved in dopamine expression and differentiation. The expression levels of DßH, AADC, VMAT2 and MAOA in SH-SY5Y cells cultured on the nanotube scaffolds for 7 days were elevated in comparison to the control cells.

Design and synthesis of C-aryl angular luotonins via a one-pot aza-Nazarov-Friedlander sequence and their Topo-I inhibition studies along with C-aryl vasicinones and luotonins.

A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.

Synthesis and biofilm inhibition studies of 2-(2-amino-6-arylpyrimidin-4-yl)quinazolin-4(3H)-ones.

Synthesis of novel 4(3H)-quinazolinonyl aminopyrimidine derivatives has been achieved via quinazolinonyl enones which in turn were obtained from 2-acyl-4(3H)-quinazolinone. They have been assayed for biofilm inhibition against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative bacteria (Acinetobacter baumannii). The analogues with 2,4,6-trimethoxy phenyl, 4-methylthio phenyl, and 3-bromo phenyl substituents (5h, 5j & 5k) have been shown to inhibit biofilm formation efficiently in MRSA with IC50 values of 20.7-22.4 µM). The analogues 5h and 5j have demonstrated low toxicity in human cells in vitro and can be investigated further as leads.

The hydro-chloride salt of 4-hy-droxy-N,N-di-n-propyl-tryptamine (4-HO-DPT).

The title compound, 4-hy-droxy-N,N-di-n-propyl-tryptammonium (4-HO-DPT) chloride {systematic name: N-[2-(4-hy-droxy-1H-indol-3-yl)eth-yl]-N-propyl-propan-1-aminium chloride}, C16H25N2O+·Cl-, has a singly protonated trypt-ammonium cation and one chloride anion in the asymmetric unit. A series of N-H⋯Cl and O-H⋯Cl hydrogen bonds connect the ions together in ladder chains along [010].

Synthesis of C-Ring-Substituted Vasicinones and Luotonins via Regioselective Aza-Nazarov Cyclization of Quinazolinonyl Enones.

A facile synthesis of C-ring substituted luotonins and vasicinones has been realized via a super-acid-mediated aza-Nazarov cyclization of quinazolinonyl enones. The regioselectivity of the cyclization is highly dependent on proton availability in the reaction medium.

Facile synthesis of 3-substituted imidazo[1,2-a]pyridines through formimidamide chemistry.

A facile entry to 3-aryl/alkenyl/alkynyl substituted imidazo[1,2-a]pyridines (3a-p, 6a-d & 9a-9e) has been developed from readily available benzyl/allyl/propargyl halides and 2-amino pyridines as substrates via formimidamide chemistry that is devoid of caustic or expensive reagents, such as transition metal complexes. Quantum chemical calculations performed to understand the underlying mechanism of the transformation revealed a preference for intramolecular Mannich-type addition over pericyclic 1,5-electrocyclization for the systems reported herein that enable a Baldwin allowed 5-exo-trig cyclization instead of a formally anti-Baldwin 5-endo-trig process.