Table 1.
Summarization of the spacers utilized in the studies involved in this review
| Bivalent compound |
Spacer | Length of spacer (atoms) |
Target | In vitro activity | In vivo activity |
|---|---|---|---|---|---|
| KDN21 |  |
21 | δ–κ-opioid receptor heterodimer | Ki = 0.3 ± 0.0 nM (co-expressed δ–κ); Ki = 63 ± 6.3 nM (mixed δ + κ) | Agonist activity (ED50 =31 pmol) |
| MCC22 |  |
22 | MOR–CCR5a heterodimer | - | Antinociceptive activity (ED50 = 0.015 or 0.019 pmol/mouse) |
| AK-15b |  |
6 | ER homodimer | 38% ER downregulatory potency at 1 μM in MCF-7 cells | - |
| VZMC001 |  |
21 | MOR–CCR5a heterodimer | MOR (Ki = 51.8 nM, IC50 = 40.0 nM); CCR5 (Ki = 239 nM, IC50 = 126 nM) | - |
| - |  |
22–88 | D2R-NTS1R heterodimer | Binding affinities in the picomolar range for cells co-expressing D2R and NTS1R | - |
| MQ-22a |  |
20 | mGluR5–D2R heterodimer | D2R (Ki = 50 ± 6.4 nM); D2R-mGluR5 (Ki = 13 ± 3.6 nM); mGluR5 (Ki = 2.3 ± 0.5 nM); D2R-mGluR5 (Ki= 1.1 ± 0.2 nM) | - |
| SG-15 |  |
14 | 5-HT2AR homodimer | Inhibiting 5-HT (1 μM) induced calcium flux (IC50 = 36.5 nM) | - |
| CS-6c |  |
5-HT2AR homodimer | ERK1/2 activation (IC50 = 178 nM); 5-HT2AR (Ki = 5.8 nM) | Suppress hyperactivity | cocaine-evoked in a time-dependent manner (2 mg/kg) |
| CJL-1-124 | PEDG20 | 20 | hMC4R homodimer | Stimulating the cAMP signaling pathway (EC50 = 4.7 nM) | - |
| DP-13 |  |
25 | D2R homodimer | KDB1 = 0.021 nM | - |
| SD-11 |  |
12 | MOR-CBR heterodimer | [3H]DAMGO (Ki = 18 nM); [3H]JWH-018 (Ki = 34 nM); Emax = 147%, EC50 = 215 nM | Antiallodynic effect (20 μg dose) |
| VZMX001 |  |
20 | MOR-CXCR4 heterodimer | MOR (Ki = 25.4 nM, IC50 = 61.9 nM); CXCR4 [IC50 = 17.2 μM (binding affinity), IC50 = 3.3 μM] | - |
| D24M |  |
24 | MOR-DOR heterodimer | MDOR potency (0.85 nM), binding affinity (0.63 nM) | Reduced acute and chronic morphine withdrawal behaviors |
| MQ-12d |  |
18 | MOR-D2-likeR heterodimer | MOR (Ki = 16 nM), D2R (Ki = 22 nM), MOR-D2R (Ki = 101 nM); MAPK phosphorylation (EC50 = 0.12 μM) | - |
a
5-HT2AR, serotonin-2A receptor; CBR, ; CCR5, C-C chemokine receptor type 5; CXCR4, C-X-C chemokine receptor type 4; D2R, dopamine D2 receptor; D2-likeR, D2R and D4R; DOR, δ-opioid receptor; ER, estrogen receptor; hMC4R, human melanocortin-4 receptor; MAPK, mitogen-activated protein kinase; MDOR, MOR-DOR heterodimer; mGluR5, metabotropic glutamate receptor 5; MOR, μ-opioid receptor; NTS1R, neurotensin NTS1 receptor.