Paul Blundell

Technepine: A high-affinity 99mtechnetium probe to label the dopamine transporter in brain by SPECT imaging

Increasing evidence suggests that the dopamine transporter, localized on dopamine neurons, is a marker for a number of physiological and pathological states (KaufmanandMadras, 1991,1993; Madras et al., 1990a, Schoemaker et al., 1985; Singer et al., 1991). With the development of sensitive probes, brainimaging and mea- surement of the transporter have become feasible in re- cent years (Brownell et al., in press; Innis et al., 1991; Frost et al., 1993; Madras et al., 1991; Morns et al., sub- mitted; Seibyl et al., 1995; van Dyke et a1.,1995; Wonget al., 1993,1995). Drugs of many chemical classes, includ- ing cocaine, bind to the dopamine transporter (Seeman, 1993). Nevertheless, effective imaging agents have been developed almost exclusively from the phenyltropane analogue of cocaine WIN 35,428 or CFT, a potent dopa- mine transport inhibitor (Clarke et al., 1973; Heikkila et al., 1979). The impetus for developing [llC]WIN 35,428 as a PET ligand (Hantraye et al., 1992; Madras, 1994; Madras et al., 1991, 1994; Wong et al., 1993; Meltzer et al., 1993) and y-emitting analogues for SPECT imaging (e.g., RTI-55, the 4-iodophenyl analogue of WIN 35,428, Canfield et al., 1990; Boja et al., 1991; Innis et al., 1991) arose directly from our observations of the binding of WIN 35,428 to the dopamine transporter. Unlike previ- ous dopamine transport inhibitors (noncocaine conge- ners) proposed for brain imaging(Kuhar et a1.,1990), the radiolabeled form of WIN 35,428 binds to the dopamine transporter in brain striatum with very low levels of non- specific binding (Madras et al., 1989a,b) and distributes principally to dopamine-rich regions of brain, as we re- ported in 1989 (Canfield et al., 1989) and subsequently (Canfield et al., 1990; Kaufman et al., 1991; Kaufman and Madras, 1992). SPECT imaging techniques are more practical than PET for routine clinical studies because of the lesser

The invention of radical reactions. Part XXI. Simple methods for the radical deoxygenation of primary alcohols.

Abstract Novel radical-chain deoxygenations of primary alcohols are described. The alcohols are acylated with the reagents pentafluorophenyl chlorothionoformate, 2,4,6-trichlorophenyl chlorothionoformate and 4-fluorophenyl chlorothionoformate and the intermediate thionocarbonates are deoxygenated with tributyltin hydride, triphenylsilane, diphenylsilane or phenylsilane in high-yielding reactions.

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.

Bicyclo[3.2.1]octanes: Synthesis and inhibition of binding at the dopamine and serotonin transporters

Herein we report the synthesis of a series of bicyclo[3.2.1]octanes and their binding characteristics at the dopamine and serotonin transporters. The data confirm that a heteroatom at position 8 of the tropane nucleus is not a prerequisite for binding since the bicyclo[3.2.1]octanes prove potent inhibitors of both transporters. Therefore the three-dimensional topology of the ligand may be more important than specific functionality with respect to stereospecific binding at the acceptor site.

Acyl derivatives of hydroxamic acids as a source of carbon radicals

Abstract Acyl derivatives of a number of hydroxamic acids are smoothly reduced by tributyltin hydride with initiation by AIBN to give the corresponding nor-hydrocarbons in a new radical chain reaction.

3-Aryl-2-carbomethoxybicyclo[3.2.1]oct-2-enes inhibit WIN 35,428 binding potently and selectively at the dopamine transporter

The search for medications for cocaine abuse has focused upon the design of potential cocaine antagonists or cocaine substitutes which interact at the dopamine transporter of mammalian systems. This manuscript describes the synthesis and biological evaluation of 8-substituted 2-carbomethoxy-3-arylbicyclo[3.2.1]oct-2-enes. These compounds prove potent and selective inhibitors of the dopamine transporter. Their selectivity results primarily from a reduced inhibitory potency toward the serotonin transporter. This work supports the notion that the orientation of the 3-aryl ring in the bicyclo[3.2.1]octane system affects the interaction of these molecules with the serotonin transporter far more markedly than it affects the interaction with the dopamine transporter.

Design and synthesis of an irreversible dopamine-sparing cocaine antagonist☆

Cocaine is a powerful reinforcer and stimulant that binds to specific recognition sites associated with monoamine transporters in the mammalian brain. The search for a functional antagonist to the addictive properties of cocaine has focused on the discovery of a molecule that can inhibit cocaine binding to the dopamine transporter (DAT) but continue to allow dopamine transport by the DAT. No such dopamine-sparing cocaine antagonist has been reported and it is becoming evident that dopamine-sparing antagonism of the pharmacological effects of cocaine by a classical antagonist may not be possible. Herein we present a new concept for the design of dopamine-sparing cocaine antagonists. A unique approach is utilized to deliver an inhibitor that binds irreversibly to the DAT, then cleaves and leaves behind a small fragment attached to the DAT that blocks access by cocaine but permits dopamine transport. The design of these compounds takes advantage of a cysteinyl sulfhydryl group in the DAT. This group is hypothesized to attack the incoming inhibitor and lead to selective inhibition of the cocaine binding site while sparing dopamine transport. This concept of a mechanism based irreversible dopamine-sparing cocaine antagonist has now been demonstrated to be viable and, as example, the unsaturated 6 showed inhibition of cocaine (63%) at the DAT after 24h incubation, while at that point considerably less inhibition of dopamine is manifested (23%). In contrast, the epoxide 7 showed a greater inhibition of dopamine reuptake than cocaine binding at 24h (68% versus 18%).

The invention of radical reactions. Part XXVIII a new very photolabile O-acyl thiohydroxamic acid derivative as precursor of carbon radicals

Abstract A new thiohydroxamic acid was synthesized and found to be an excellent generator of carbon radicals via its O-acyl derivatives.

Synthesis and antifungal activity of the 2,2,5-tetrahydrofuran regioisomers of SCH 51048.

The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.

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.