Mario D. Gonzalez

A general method for C3 reductive alkylation of indoles

Abstract General indole C 3 reductive alkylation conditions have been developed. The scope of this reaction includes C 2 unsubstituted indoles, aryl and alkyl aldehydes, as well as N–H and N -alkyl indole substrates.

Nitrogen‐based drugs are not essential for blockade of monoamine transporters

In brain, monoamine transporters are principal targets of widely used therapeutic drugs including antidepressants, methylphenidate (Ritalin), and the addictive drug cocaine. Without exception, these transport blocking agents contain an amine nitrogen. A prevalent view and untested promise is that an amino nitrogen is needed to bind to the same counterion on the transporter as does the amino nitrogen of the monoamine neurotransmitter. We report that several compounds without nitrogen (8‐oxa‐bicyclo‐3‐aryl‐[3.2.1] octanes, or aryloxatropanes) are active at monoamine transporters. One of these, tropoxane (O‐914), bound with high affinity to the dopamine (IC???: 3.35 ± 0.39 nM), serotonin (IC??? 6.52 ± 2.05 nM), and norepinophrine (IC???: 20.0 ± 0.3 nM) transporters in monkey brain, the human striatal dopamine transporter (IC???: 5.01 ± 1.74 nM), and blocked dopamine transport (IC???: 7.2 ± 3.0 nM) in COS‐7 cells transfected with the human dopamine transporter. These unique compounds require a revision of current concepts of the drug binding domains on monoamine transporters, open avenues for discovery of a new generation of drugs and raise the issue of whether mammalian transporters and receptors may respond to, as yet, undiscovered non‐amine bearing neurotransmitters or drugs.

A ring opening rearrangement reaction of 6β-hydroxytropinone

Abstract A ring opening rearrangement reaction of 6β-hydroxytropinone resulted in the novel bicyclic oxazolidine 2. Hydrolysis of 2 with hydrochloric acid in methanol provided 6β-hydroxytropinone and 6α-hydroxytropinone.

Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter

Methamphetamine, a human vesicular monoamine transporter 2 (VMAT2) substrate, releases dopamine, serotonin, and norepinephrine from vesicles into the cytosol of presynaptic neurons and induces reverse transport by the monoamine transporters to increase extracellular neurotransmitters. Currently available radioligands for VMAT2 have considerable liabilities: The binding of [3H]dihydrotetrabenazine ([3H]DHTB) to a site on VMAT2 is not dependent on ATP, and [3H]reserpine binds almost irreversibly to VMAT2. Herein we demonstrate that several arylpiperidinylquinazolines (APQs) are potent inhibitors of [3H]reserpine binding at recombinant human VMAT2 expressed in HEK-293 cells. These compounds are biodiastereoselective and bioenantioselective. The lead radiolabeled APQ is unique because it binds reversibly to VMAT2 but does not bind the [3H]DHTB binding site. Furthermore, experimentation shows that several novel APQ ligands have high potency for inhibition of uptake by both HEK-VMAT2 cells and mouse striatal vesicles and may be useful tools for characterizing drug-induced effects on human VMAT2 expression and function.