Four Novel Synthetic Tryptamine Analogs Induce Head-Twitch Responses and Increase 5-HTR2a in the Prefrontal Cortex in Mice.

Tryptamines are monoamine alkaloids with hallucinogenic properties and are widely abused worldwide. To hasten the regulations of novel substances and predict their abuse potential, we designed and synthesized four novel synthetic tryptamine analogs: Pyrrolidino tryptamine hydrochloride (PYT HCl), Piperidino tryptamine hydrochloride (PIT HCl), N,N-dibutyl tryptamine hydrochloride (DBT HCl), and 2-Methyl tryptamine hydrochloride (2-MT HCl). Then, we evaluated their rewarding and reinforcing effects using the conditioned place preference (CPP) and self-administration (SA) paradigms. We conducted an open field test (OFT) to determine the effects of the novel compounds on locomotor activity. A head-twitch response (HTR) was also performed to characterize their hallucinogenic properties. Lastly, we examined the effects of the compounds on 5-HTR1a and 5-HTR2a in the prefrontal cortex using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. None of the compounds induced CPP in mice or initiated SA in rats. PYT HCl and PIT HCl reduced the locomotor activity and elevated the 5-HTR1a mRNA levels in mice. Acute and repeated treatment with the novel tryptamines elicited HTR in mice. Furthermore, a drug challenge involving a 7-day abstinence from drug use produced higher HTR than acute and repeated treatments. Both the acute treatment and drug challenge increased the 5-HTR2a mRNA levels. Ketanserin blocked the induced HTR. Taken together, the findings suggest that PYT HCl, PIT HCl, DBT HCl, and 2-MT HCl produce hallucinogenic effects via 5-HTR2a stimulation, but may have low abuse potential.

Methiopropamine, a methamphetamine analogue, produces neurotoxicity via dopamine receptors.

Methiopropamine (MPA) is structurally categorized as a thiophene ring-based methamphetamine (MA) derivative. Although abusive potential of MPA was recognized, little is known about the neurotoxic potential of MPA up to now. We investigated whether MPA induces dopaminergic neurotoxicity, and whether MPA activates a specific dopamine receptor. Here, we observed that treatment with MPA resulted in dopaminergic neurotoxicity in a dose-dependent manner. MPA treatment potentiated oxidative parameters (i.e., increases in the level of reactive oxygen species, 4-hydroxynonenal, and protein carbonyl), M1 phenotype-related microglial activity, and pro-apoptotic property (i.e., increases in Bax- and cleaved caspase-3-expressions, while a decrease in Bcl-2-expression). Moreover, treatment with MPA resulted in significant impairments in dopaminergic parameters [i.e., changes in dopamine level, dopamine turnover rate, tyrosine hydroxylase (TH) levels, dopamine transporter (DAT) expression, and vesicular monoamine transporter-2 (VMAT-2) expression], and in behavioral deficits. Both dopamine D1 receptor antagonist SCH23390 and D2 receptor antagonist sulpiride protected from these neurotoxic consequences. Therefore, our results suggest that dopamine D1 and D2 receptors simultaneously mediate MPA-induced dopaminergic neurodegeneration in mice via oxidative burdens, microgliosis, and pro-apoptosis.

Natural products hybrids: 3,5,4'-Trimethoxystilbene-5,6,7-trimethoxyflavone chimeric analogs as potential cytotoxic agents against diverse human cancer cells.

Cancer still represents a major global health problem. All currently available anticancer agents have disadvantages like resistance or side effects. Therefore, introduction of novel anticancer agents is needed. Intrigued by the high success rate for natural products-based drug discovery, we designed and synthesized antiproliferative chemical entities as hybrids of two natural products; 3,5,4'-trimethoxystilbene and 5,6,7-trimethoxyflavone. To probe the spectrum of the synthesized compounds, in vitro evaluation was conducted against nine panels representing major cancer diseases. The results revealed the hybrid analogs 4f, 4h, 4k and 4q as promising broad-spectrum anticancer lead compounds eliciting high growth inhibition of several cell lines representing multiple cancers diseases. Evaluation of the promising lead compounds against normal human cell lines suggested a selective cytotoxic effect on cancer cells. Mechanistic investigation of the cytotoxic activity of compound 4f in human cervical cancer HeLa cells showed that it triggers cell death through induction of apoptosis. As a whole, this study presents the natural products hybrid analogs 4f, 4h, 4k and 4q as potential lead compounds for further development of novel anticancer therapeutics.

Design, synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids.

Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad-spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI50 values was in the ranges of 24.7-46.9 µM and 26.8-43.1 µM for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line.

1H-NMR and 13C-NMR dataset for some oxidative metabolites of CRA13 and their analogs.

CRA13 (CB-13; SAB-378) is a dual CB1R/CB2R agonist cannabinoid agent developed by Novartis Pharma. Upon administration, it undergoes metabolism to oxidative metabolites. Herein, the 1H-NMR and 13C-NMR dataset of some oxidative metabolites and analogs thereof are presented for further analysis and comparison purposes, for whom may be interested.

Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB2R affinity.

CRA13; a peripheral dual CB1R/CB2R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1R and CB2R activity revealed the alcohol metabolite 8c as a more potent and more effective CB2R ligand with attenuated CB1R affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CB2R affinity and reduced CB1R affinity. The CB2R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.