Putative α7-selective agonists (see Figure 2 for structures)
| Compound | Summary* | Reference |
|---|---|---|
| A-582941 | Expression system: Xenopus oocytes and GH4C1 cells for α7. α3* and α4* receptors in HEK cells with Ca2+ FLIPR assay. Binding studies with human brain membranes. Effects on 5HT3 receptors: not studied. Summary: partial agonist of α7 with relatively little activation of other nAChR tested. Positive cognitive effects (inhibitory avoidance) in rats blocked by NS6740. {Total of 12 compounds evaluated.} | (Tietje et al., 2008) (Briggs et al., 2009) |
| ABT-107 | Expression system: oocyte α7 compared with α3β4 α4β2 and α4β4 in cell lines. Also tested in brain slices. Effects on 5HT3 receptors: no activity. Summary: efficacious (80%) partial agonist for human α7 (EC50 = 50–90 nM). Protected cultured cortical neurons from glutamate toxicity. Numerous follow-up studies. | (Malysz et al., 2010) |
| AZD0328 | Expression systems: receptor binding with transfected HEK cells compared with nicotine binding in rat brain, PC12 cells, or muscle-type BC3H1 cells. Xenopus oocytes rat and human α7, rat and human α4β2, and human α3β4. Effects on 5HT3 receptors: partial agonist (12%) EC50 = 474 ± 173 nM. Summary: efficacious (64%) partial agonist for human α7 (EC50 = 150 ± 40 nM). Low efficacy on α4β2 receptors. Positive effects in NOR. Increases activity of midbrain dopamine neurons. Some follow-up studies on memory and dopaminergic denervation. | (Sydserff et al., 2009) |
| AQW051 | Expression system: binding studies in SH-SY5Y cells and rat brain membranes. Xenopus oocytes voltage clamp for α7, all others FLIPR from cell lines. No actual data shown. nAChR subtypes studied: α7, α2β2, α3β2, α3β4,α2β4,α3β4, α4β4. Effects on 5HT3 receptors: nature of activity ill-defined, claimed 500-fold less potent than for α7. Summary: claimed efficacy for α7 of 73%, but no data shown, claimed EC50 ≈ 40 nM. Positive effects with NOR and water-maze performance with aged rats. Pharmacokinetics and tolerability were evaluated in three phase I placebo-controlled studies in 180 healthy subjects with relatively few adverse effects. Numerous follow-up studies. | (Feuerbach et al., 2015) |
| BMS-933043 | Expression system: cell line FLIPR. Methods described only in supplemental material, and actual no data shown in manuscript or supplement. Binding in HEK cell membranes. Electrophysiology with patch-clamp and dynaflow (Cellectricon) perfusion system. nAChR subtypes studied: α1β1γε, α3β4, α4β2, α7. Effects on 5HT3 receptors: putatively low potency compared with α7. Summary: impossible to evaluate the quality of the data. This is a particular concern of the α7 electrophysiology. Positive effects reported with NOR. {Total of three compounds evaluated.} | (King et al., 2017a) |
| BMS-902483 | Expression system: Binding with α7-transfected cells. Electrophysiology on α7 with patch-clamp and dynaflow (Cellectricon) perfusion system. Limited data shown. nAChR subtypes studied: α1β1γε, α3β4, α4β4, α7. Binding data only for non-α7. Effects on 5HT3 receptors: sntagonist IC50 = 0.51 µM. Summary: α7 partial agonist (62%) EC50 = 0.24 µM. Limited data on selectivity. Positive effects on NOR, auditory gating, and other behavioral tests. Augmented LTP. NOR effects blocked by NS6740. {Total of 58 compounds evaluated.} | (Pieschl et al., 2017) (Cook et al., 2016) |
| BrIQ17B | Expression system: Xenopus oocytes for α7 (peak currents) and other subtypes. Radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons also used. nAChR subtypes studied: α3β4, α4β2, α7, and GABAA receptors. Effects on 5HT3 receptors: inhibition only at high conc. Summary: partial (64%) agonist, EC50 1.8 ± 0.2 (based on peak currents). Lower conc. inhibited ACh-evoked responses. Inconsistency in data since in one case 0.3 µM produced no apparent response when applied prior to ACh, yet in CRC study 0.3 µM produced approximately 7% maximal response. | (Tang et al., 2015) |
| CP-810,123 | Expression system: binding assay for rat r7 nAChRs expressed in GH4C1 cells using [125I]BTX as the radioligand. High-throughput FLIPR-based functional assay that used SH-EP1 cells expressing the α7/5-HT3 chimera. nAChR subtypes studied: only α7/5HT3 chimera studied directly α4β2, and α3β4 inferred from binding studies with rat brain or IMR32 cells, respectively. Effects on 5HT3 receptors: binding assay for human 5-HT3 receptors expressed in HEK293 cells using [3H]LY278584 as the radioligand. Summary: Large family off compounds studies with CP-810,123 identified as most promising lead. Data based on chimera reported an EC50 on this unnatural receptor of 16.4 nM with an Imax 195% that of 50 µM nicotine. No data are shown. Tested in auditory gating yielded inconclusive results. {Total of 43 compounds evaluated.} | (O'Donnell et al., 2010) |
| DPP compounds | Expression system: Binding with AChBPs, transfected cells, and Xenopus oocytes. nAChR subtypes studied: α7 α4β2. Effects on 5HT3 receptors: confirmed no activity with cell-based neurotransmitter fluorescent engineered reporters. Summary: Compounds have been described as “noncanonical agonists” since their structures defy normal models of the nAChR pharmacophore. They were initially identified by their binding to molluscan AChBP. Activity and selectivity confirmed with cell-based fluorescence activity with the PAM PNU-120596 used to increase α7 signals. Selective activation of α7 confirmed with TEVC in Xenopus oocytes for a subset of the compounds. Efficacy ranged from 40%–80% with submicromolar potencies with a range of desensitizing activities. {Total of 75 compounds evaluated.} | (Kaczanowska et al., 2017; Camacho-Hernandez et al., 2019) |
| EVP-6124 (encenicline) | Expression system: binding with rat brain membranes, TEVC in Xenopus oocytes. nAChR subtypes studied: α7, α4β2, α3β4, and muscle-type receptors. Effects on 5HT3 receptors: Binding studies showed that EVP-6124 inhibited the 5-HT3 receptor by 51% at 10 nM. Summary: a reported EC50 of 0.16 µM based on peak currents, suggesting more potent activity on 5HT receptors than α7. IMax estimation limited by protocol, which permitted cumulative desensitization. Claimed to have potentiating activity at low conc.; however, see Figure 3. Active in NOR and other cognitive tests. Numerous follow-up studies. | (Prickaerts et al., 2012) |
| FRM-17874 | Expression systems: binding studies and Xenopus oocyte TEVC. nAChR subtypes studied: α7 only. Effects on 5HT3 receptors: Evaluated in binding studies that showed significant inhibition. TEVC in oocytes showed an IC50 of 3.2 ± 2.4 nM. Summary: analog of EVP-6124, also reputed to have a potentiating effect at low conc. TEVC in oocytes indicated a EC50 of 0.42 ± 0.17 µM, but data were of insufficient quality to estimate an Imax. FRM-17874 improved novel object recognition in rats and enhanced memory acquisition and reversal learning in the mouse water T-maze and enhanced hippocampal LTP. | (Stoiljkovic et al., 2015) |
| Iwuagwu et al. Compound 31 | Expression systems: FLIPR assays of transfected cells and patch clamp for HERG and reportedly for α7, although no patch data are shown either, and no patch-clamp results reported for α7. nAChR subtypes studied: α7 only. Effects on 5HT3 receptors: IC50 for 5HT3 = 9.2 µM from FLIPR. Summary: Lead compound from a study of 4-heteroarylamino-10-azaspiro [oxazole-5,30-bicyclo[2.2.2]octanes]. EC50 for α7 of 11 nM from FLIPR. Positive effect in NOR. No apparent follow-up publications. {Total of 31 compounds evaluated.} | (Iwuagwu et al., 2017) |
| NS6784 | Expression system: Xenopus oocytes and GH4C1 cells for α7. α3* and α4* receptors in HEK cells with Ca2+ FLIPR assay. Binding studies with human brain membranes. nAChR subtypes studied: putative α3*, putative α4*, α7. Effects on 5HT3 receptors: not studied. Summary: Efficacious agonist of α7 with relatively little activation of other nAChR tested. {Total of three compounds evaluated.} | (Briggs et al., 2009) |
| SEN12333 (WAY-317538) | Expression system: GH4C1 cell line for a7 FLIPR and patch-clamp studies. Binding studies with transfected cells. nAChR subtypes studied: putative α3*, putative α4*. Effects on 5HT3 receptors: claimed inactive, no data shown. Summary: EC50 = 687 nM in FLIPR assay and 42 µM in patch-clamp study of peak currents. Data on numerous other analogs reported. {Total of 81 compounds evaluated.} | (Beinat et al., 2012, 2015) (Haydar et al., 2009) |
| SEN15924 (WAY-361789) | Expression system: FLIPR assays GH4C1 cells for α7. Transfected HEK cells for 5HT3, SH-SY5Y for putative ganglionic (α3*) receptors, and TE671 for muscle-type. nAChR subtypes studied: putative α3*, α1β1γδ, and α7. Effects on 5HT3 receptors: inhibitory activity at >30 µM. Summary: Large study of numerous analogs. Lead compound does something in FLIPR assay (no actual data shown) EC50 = 0.18 µM ± 0.01. Positive effects in NOR and auditory gating reported. {Total of 25 compounds evaluated.} | (Zanaletti et al., 2012b) |
| SEN78702 (WYE-308775) | Expression system: FLIPR assays: GH4C1 cells for α7. Transfected HEK cells for 5HT3, SH-SY5Y for putative ganglionic (α3*) receptors and TE671 for muscle-type transfected CHO cells for HERG channels. nAChR subtypes studied: putative α1β1γδ, α3*4, α7. Effects on 5HT3 receptors: reportedly no agonist activity. Antagonist activity not studied. Summary: hypothetically, a full agonist in FLIPR assay, but relative to what standard is not clear EC50 = 125 ± 70 nM. Potency values from such assays are typically at least 10-fold higher than those from electrophysiology. No agonist activity detected on other subtypes. Antagonist activity not studied. Positive effects in NOR, and acoustic startle response reported. {Total of 12 compounds evaluated.} | (Zanaletti et al., 2012b) |
| (R)-7-methyl-N-quinuclidin-3-yl)pyrrolo[1,2-a]quinoline-2-carboxamide (Compound 10a) | Expression system: Xenopus oocytes. nAChR subtypes studied: α3β4, α4β2, and α7. Effects on 5HT3 receptors: Very effective antagonist of 5HT3a expressed in oocytes. IC50 ≈ 800 nM, full inhibition with 10 µM. Summary: Very little data presented. EC50 for α7 of approximately 2 µM with roughly 70% efficacy (peak currents). MLA blocks, PNU-120596 potentiates, and MLA. Preapplications of low conc. inhibited ACh responses with an IC50 of 21. 2 ± 1.3 nM. No apparent follow-up publications at the time of this writing. {Total of 32 compounds evaluated.} | (Xue et al., 2019) |
| TC-7020 | Expression system: Xenopus oocytes for α7. TE671 and SH-SY5Y and SH-EP1 cells for other nAChRs in FLIPR assays. Also, brain membranes for binding studies. nAChR subtypes studied: α1β1γδ (TE671 cells), putative α3 (SH-SY5Y) α4* (SH-EP1), and α7 in oocytes. Effects on 5HT3 receptors: not studied. Summary: Authors state that TC-7020 is an efficacious partial (68%) agonist for α7 net charge responses, but data are not shown, nor is an EC50 provided. Oocyte work was done in the laboratory of an author of this review (R.L.P.), and although Marrero et al. say that an EC50 was not determined, the readers of this review may be assured that it was. There were minimal responses of other subtypes in FLIPR assay compared with nicotine. It may be noted that in regard to the results with TE671 cells, muscle-type receptors are not calcium permeable, and nicotine is a weak agonist for this subtype. Effects measured on mediators of CAP, TNF-α, and JAK-2. | (Marrero et al., 2010) |
| TTln-1 | Expression system: fluorescence resonance energy transfer assay using cell lines expressing transfected cDNAs and a fluorescence cell reporter as well as ligand binding. nAChR subtypes studied: α4β2 and α7, also the α7/5ht chimera. Effects on 5HT3 receptors: antagonist, IC50 = 5 = 4.9 ± 2.7 µM. Summary: This is a study evaluating a family of analogs for receptor activity with a novel approach. α7 data are from either the nondesensitizing α7/5HT chimera or α7 in the presence of the PAM PNU-120596. Therefore, the estimated EC50 of 570 ± 130 nM is probably too low by at least a factor of 10, and efficacy cannot be evaluated. {Total of 24 compounds evaluated.} | (Arunrungvichian et al., 2015) |
BTX, bungarotoxin; CRC, concentration response curve; HEK, human embryonic kidney; HERG, human Ether-à-go-go-Related Gene; LTP, long-term potentiation; TEVC, two-electrode voltage-clamp.