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NEUROPHARMACOLOGY

Differential Activity of the Nerve Growth Factor (NGF) Antagonist PD90780 [7-(Benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic Acid] Suggests Altered NGF-p75^NTR Interactions in the Presence of TrkA

Department of Physiology, Queen's University, Kingston, Ontario, Canada (A.C., G.M.L., I.L.S., G.M.R.); Division of Medical Sciences, Northern Ontario Medical School, Sudbury and Thunder Bay, Ontario, Canada (G.M.R.); and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (R.J.R.)

The neurotrophin nerve growth factor (NGF) binds to two receptor types: the tyrosine kinase receptor TrkA and the common neurotrophin receptor p75^NTR. Although many of the biological effects of NGF (such as neuronal growth and survival) are associated with TrkA activation, p75^NTR also contributes to these activities by enhancing the action of TrkA when receptors are coexpressed. The NGF antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxlic acid] interacts with NGF, preventing its binding to p75^NTR. In this study, the actions of this compound are further explored, and it is found that PD90780 is not able to inhibit the binding of either brain-derived neurotrophic factor or neurotrophin-3 to p75^NTR, consistent with the direct interactions of the antagonist with NGF. In addition, we demonstrate that the ability of PD90780 to inhibit NGF-p75^NTR interactions is lower when receptors are coexpressed, compared with when p75^NTR is the only neurotrophin receptor expressed. These results suggest that the interaction between NGF and the p75^NTR receptor is altered when TrkA is coexpressed. This alteration can be exploited in the development of antagonists that will selectively inhibit the pro-apoptotic actions of p75^NTR when expressed in the absence of TrkA, although having less effect on the pro-survival effects of p75^NTR mediated by enhanced TrkA activation.

Address correspondence to: Dr. Gregory M. Ross, Department of Physiology, Queen's University, Kingston, ON, Canada K7L 3N6. E-mail: rossg{at}post.queensu.ca

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