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P Blundell

Publications and source records attributed to P Blundell.

11 recordsLinked to original sources
PubMed2001

Lesions of the basolateral amygdala disrupt selective aspects of reinforcer representation in rats.

The amygdala is known to play a role in learning about motivationally significant events. We investigated this role further by examining the effects of excitotoxic lesions of the basolateral amygdala on the ability of rats to use instrumental outcomes to direct responding (the differential outcomes effect) and on the ability of Pavlovian cues to modulate instrumental performance based on shared outcomes (reinforcer-selective Pavlovian-to-instrumental transfer). We found that basolateral amygdala (BLA) lesions did not affect the ability of rats to learn a basic instrumental conditional discrimination, but did disrupt the ability of differential outcomes to facilitate acquisition. In Pavlovian-to-instrumental transfer, BLA lesions did not disrupt the basic enhancement of instrumental performance but did abolish the reinforcer specificity of that enhancement. These results suggest that the BLA is involved in the representation of the sensory aspects of motivationally significant events.

Amygdala↗
PubMed2001

Synthesis of 6- and 7- hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters.

Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). Inhibition of the DAT causes an increase of dopamine in the synapse with a resultant activation of postsynaptic receptors. The rapid onset and short duration of action of cocaine contribute to its high addictive potential. Consequently, the design of tropane analogues of cocaine that display longer onset times on the DAT and extended duration of action is driven by the need to develop cocaine medication. This study extends the exploration of bridge hydroxylated azabicyclo[3.2.1]octanes (tropanes). A series of 6- and 7-hydroxylated tropanes was prepared and evaluated biologically. Structure activity relationships lead to the following conclusions. Bridge hydroxylated tropanes retain biological enantioselectivity but display higher DAT versus SERT selectivity, particularly for the 3 alpha-aryl compounds as compared with the 3beta-aryl compounds, than the bridge unsubstituted analogues. The 7-hydroxyl compounds are more potent at the DAT than their 6-hydroxyl counterparts. The general SAR of the tropanes is maintained and the rank order of potencies based on substitution at the C3 position remains 3,4-dichloro > 2-naphthyl > 4-fluoro > phenyl.

Animals↗
PubMed2000

2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters.

Cocaine is a potent central nervous system stimulant with severe addiction liability. Its reinforcing and stimulant properties derive from inhibition of monoamine transport systems, in particular the dopamine transporter (DAT). This inhibition results in an increase in synaptic dopamine with subsequent stimulation of postsynaptic dopamine receptors. A wide variety of ligands manifest potent inhibition of the DAT, and these ligands include 3-aryltropane as well as 8-oxa-3-aryltropane analogues of cocaine. There has been considerable effort to determine structure-activity relationships of cocaine and congeners, and it is becoming clear that these inhibitors do not all interact with the DAT in the same manner. The functional role of the 8-heteroatom is the focus of this study. We describe the preparation and biology of a series of 2-carbomethoxy-3-arylbicyclo[3.2.1]octane analogues. Results show that methylene substitution of the amine or ether function of the 8-hetero-2-carbomethoxy-3-arylbicyclo[3.2.1]octanes yields potent inhibitors of monoamine transport. Therefore neither nitrogen nor oxygen are prerequisites for binding of tropane-like ligands to monoamine transporters.

Animals↗
PubMed2000

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.

Animals↗
PubMed1999

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.

Bridged Bicyclo Compounds↗
PubMed1997

2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters.

Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing and stimulant properties have been associated with its propensity to bind to monoamine transporter systems. It has generally been assumed that the amino function on monoamines is a requirement for binding to monoamine transporters. In particular, the 8-amino function on the tropane skeleton of cocaine and cocaine analogs has been assumed to provide an ionic bond to the aspartic acid residue on the dopamine transporter (DAT). We have prepared the first 8-oxa analogs of the 3-aryltropanes (WIN compounds) and have found that the 3 beta-(3,4-dichlorophenyl) (6g) and 3 alpha-(3,4-dichlorophenyl) (7g) analogs are particularly potent (IC50 = 3.27 and 2.34 nM, respectively) inhibitors of the dopamine transporter. We now describe the synthesis and biology of the family of 2-carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes and demonstrate that an amino nitrogen is not required for binding to the DAT.

Animals↗
PubMed1997

A technetium-99m SPECT imaging agent which targets the dopamine transporter in primate brain.

The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for certain neurological diseases. In particular, the DAT is depleted in Parkinson's disease, and the extent of depletion correlates with the loss of dopamine. Herein we describe the design, synthesis, and biological evaluation of technepine, the first 99mTc-labeled SPECT imaging agent which targets the dopamine transporter in striatum. We have demonstrated that the DAT can accommodate a chelating unit attached to the 8-amine function of a tropane skeleton. Further, we have demonstrated for the first time that a molecule can be designed to carry the radionuclide 99mTc across the blood-brain barrier in sufficient quantity to obtain in vivo images of the striatum in monkeys. This advance will undoubtedly lead to the design of new receptor and transporter-mediated 99mTc agents which can label specific transporter and receptor targets in the central nervous system.

Animals↗
PubMed1996

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 premise is that an amine nitrogen is needed to bind to the same counterion on the transporter as does the amine 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 (0-914), bound with high affinity to the dopamine (IC50: 3.35 +/- 0.39 nM), serotonin (IC50: 6.52 +/- 2.05 nM), and norepinephrine (IC50: 20.0 +/- 0.3 nM) transporters in monkey brain, the human striatal dopamine transporter (IC50: 5.01 +/- 1.74 nM), and blocked dopamine transport (IC50: 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.

Animals↗
PubMed1989

The nonextractable tined endocardial pacemaker lead.

With the advent of the tined pacemaker electrode to improve endocardial fixation, increasing difficulty in extracting them when needed has resulted in reports of serious complications. The authors reviewed their experience between January 1975 and January 1985. During this 10 year period, 942 pacemakers were inserted and 73 were reoperated upon. In the reoperations, repositioning or removal of tined electrodes was attempted 28 times. Repositioning or removal was not possible in 12 of the 28 cases (43%). In 22 of 28, the attempts to remove tined leads were carried out more than one month after the original implantations and in this group the failure rate was 54.5% (12 of 22). All attempts of removal within one month of implantation were successful (six of six). No leads were retained during the period between January 1984 and January 1985. All 12 retained leads were followed-up for five years, five of which were retained in the presence of pacemaker pocket infections. After removal of the power pack and lead distal to the cephalic or subclavian vein inlet, control of infection was achieved in all five cases. One patient was noted to have the retained lead migrate into the right pulmonary artery but was asymptomatic at 35 months after catheter migration was detected. Until now, no thoracotomy for lead extraction has been required in this series.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrodes, Implanted↗
PubMed1987

Apomorphine-induced penile tumescence in impotent patients--preliminary findings.

Apomorphine (Apo), a short acting dopamine (DA) receptor agonist induces penile erections in normal subjects. The erectile response to one or more doses of Apo HCl (0.25, 0.5, 0.75, 1.0 mg sc) or placebo was investigated in eight impotent subjects and penile tumescence monitored using a mercury strain gauge and strip chart recording. Four patients showed a full erection with Apo and one a partial response. Distressing side effects (nausea, sweating) were associated with non-response or partial response. Three responders to Apo were treated with low doses of the long acting DA receptor agonist, bromocriptine (2.5-3.75 mg/d po); all three showed complete recovery of erectile function within two weeks. A subgroup of impotent patients may have impaired central DA function. Testing with Apo may provide a diagnostic and predictive test to identify such patients who may respond to treatment with low doses of bromocriptine or other DA receptor agonist.

Adult↗