Table 5.
Novel multivalent ligands for opioid (μ/δ) and NK-1 receptors and biological activity profiles for novel analgesics for neuropathic pain
| Compound | Binding affinity assays Ki (nM) | Efficacy (second-messenger) assays EC50 (nM)v | Functional assays IC50 (nM), Ki (nM) | |||||
|---|---|---|---|---|---|---|---|---|
| hDOR [3H]DPDPE | rMOR [3H]DAMGO | hNK1 [3H]SP | hDOR | hMOR | MVD(δ) | GPI(μ) | SPGPI Antagonist | |
| 1. H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3′,5′-Bzl(CF3)2 | 2.8 | 36 | 0.084 | 2.9 | 32 | 22 | 360 | 25 |
| 2. H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3′,5′-Bzl(CF3)2 | 1.8 | 9.7 | ND | 4.0 | 25 | 17 | 370 | 7.9 |
| 3. H-Tyr-D-Ala-Gly-Phe-Met2-Pro-Leu-Trp-NH-3′,5′-Bzl(CF3)2 | 0.66 | 16.0 | 0.0065 | 8.6 | 7.0 | 15 | 490 | 10 |
| 4. H-Tyr-D-Ala-Gly-Phe-Met2-Pro-Leu-Trp-NH-Bzl | 0.44 | 1.8 | 3.2 | 2.6 | 21 | 4.8 | 61 | 9.9 |
| 5. H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Ser(Glc)-Trp-NH-3′,5′-Bzl(CF3)2 | 3.7 | 8.0 | 0.077 | 7.9 | 18 | 13 | 520 | 1.8 |
Abbreviations: DAMGO, [D-Ala2,N-MePhe4,Gly-ol]enkephalin; DPDPE, c[D-Pen2,D-Pen5]enkephalin; GPI, guinea pig ileum; hDOR, human δ opioid receptor; hMOR, human μ opioid receptor; hNK1, human neurokinin-1 receptor; MVD, mouse vas deferens; ND, not determined; rMOR, rat μ opioid receptor; SP, substance P; SPGPI, substance P guinea pig ileum.