Antidepressant and Neuroprotective Effects of 3-Hydroxy Paroxetine, an Analog of Paroxetine in Rats.

BACKGROUND: Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy and fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 in silico for their pharmacokinetic and binding properties and in vivo for their antidepressant and potential neuroprotective effects. METHODS: In silico studies compared pharmacological properties as well as interactions of PX and 3HPX with the serotonin transporter. In vivo studies utilized an animal model of comorbid depression-Parkinson disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg PX or 3HPX. Animals were tested for motor asymmetry and locomotor activity as well as indices of anhedonia and helplessness using sucrose preference and forced swim tests, respectively. Brains of these animals were collected after the last test, and tyrosine hydroxylase-positive neurons in substantia nigra pars compacta and Iba-1-positive stained microglia in ipsilateral striatum were measured. RESULTS: In silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta, and more ramified Iba-1+ cells by 3HPX compared with PX. CONCLUSION: The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity.

Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones.

Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp3 )-H oxidation of piperidines to α,ß-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.

Selective, Catalytic, and Dual C(sp3)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions.

By using cheap and innocuous reagents, such as NaClO2, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.

Transition Metal-Free Selective Double sp(3) C-H Oxidation of Cyclic Amines to 3-Alkoxyamine Lactams.

The first chemical method for selective dual sp(3) C-H functionalization at the alpha-and beta positions of cyclic amines to their corresponding 3-alkoxyamine lactams is reported. Unlike traditional Cα-H oxidation of amines to amides mediated by transition metals, the present protocol, which involves the use of NaClO2/TEMPO/NaClO in either aqueous or organic solvent, not only allows the Cα-H oxidation but also the subsequent functionalization of the unreactive ß-methylene group in an unprecedented tandem fashion and using environmentally friendly reactants.

Stereoselective Synthesis and Antiallodynic Activity of 3-Hydroxylated Paroxetines.

The design, stereoselective synthesis and in vivo antiallodynic activity of four novel paroxetine analogs, named 3-hydroxy paroxetines (3HPXs), is reported herein. Among the novel synthesized compounds, three showed an antiallodynic effect, while (R,R)-3HPX was found to be 2.5 times more bioactive than (-)-paroxetine itself in neuropathic rats. Consequently, the current investigation not only discloses a novel promising analgesic drug, but also reveals that functionalization at the C3 position of paroxetine could be as effective as the common functionalization at either C4 or within the sesamol group.