Neurotrophins are dimeric growth factor hormones that regulate development and maintenance of central and peripheral nervous systems. 1r3 Members of this protein family include nerve growth factor (NGF), neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and neurotrophin-4/5 (NT-4/5). 1r4 They regulate growth, survival, differentiation of neurons, and many other neuroectoderm tissues. 5 Most “positive” signaling from neurotrophins is mediated by docking to tyrosine kinase (Trk) receptors, to which they bind selectively with high affinity (Kd≈ 10r11 M). 6 While the neurotrophins have selectivities (NGF for TrkA, BDNF for TrkB, and NT-3 for TrkC), they are not specific (Figure 1). For instance, NT-3 binds TrkA but with lower affinity than for TrkC. 7, 8 The rates of dissociation are slow for interactions of the Trk receptors with neurotrophins (t1/2> 10 min) and follow the order of NGF> NT-3> BDNF. 9 All the neurotrophins also bind with similar affinities (Kd≈ 10r9 M) 10 to the p75 receptor. The on and off rates for interacting with neurotrophins are much faster for the p75 receptor (t1/2≈ 3 s). 11 Current understanding of the literature indicates that the roles of the p75 receptor include promotion of apoptosis, survival, and regulation of other Trk activities. 12r18 Expression of, and presumably binding to, p75 can also determine whether NT-3 binds and activates TrkA. 19, 20 Abnormal neurotrophin action is evident in neurodegenerative diseases such as Alzheimer’s or stroke, 2, 21r26 pain/neuropathy, 27r32 and cancer. 33r39 The rationale for using Trk and/or p75 receptor agonists or antagonists for certain disorders is strong, 40 but the neurotrophins themselves have short lifetimes in vivo, induce unfavorable side effects, and are expensive to produce. 25, 26, 41, 42 Some of the undesirable side effects can be attributed to neurotrophins binding multiple receptors (NT-3: p75, TrkA, and TrkC) and activating multiple signaling pathways. 40, 43 Small, proteolytically stable molecules that specifically bind certain neurotrophin receptors are therefore highly desirable. They have potential applications in pain management, control of neuropathy, and acute (eg, stroke) or chronic (eg, Alzheimer’s disease) neurodegeneration. 44, 45 Concentration of TrkA receptors in regions of the brain means that agonistic NGF mimics have particular potential for treatment of Alzheimer’s disease. In fact, recombinant NGF has been used in clinical trials for the treatment of Alzheimer’s disease46 and for HIV-associated sensory neuropathy. 47 The TrkC receptor, however, is selectively expressed on motor neurons, and therefore, TrkC activating agents such as