Table 1.
Activity of CC12 on Receptors Related to Analgesia and/or Histamine
| Receptor/Target | Potential Anti- Analgesic Action |
Methodsh |
pA2 or % Inhib. (10 μM)g |
|---|---|---|---|
| μ opioid | Antaga | PSP/AMC | 0% / 5.3 (Fig. 8) |
| δ opioid | Antag a | PSP | 20% |
| CB1 | Antag a | AMC | 5.2 (Fig. 8) |
| NK1 and relatedk | complex f | PSP-HTS | inactivej |
| NT1 | complex e,f | PSP/MDS | 16% / 2% |
| 5HT2A | uncertain | PSP | 42% |
| 5HT2B | uncertain | PSP | 47% |
| 5HT2C | uncertain | PSP | 63% |
| NMDA (MK801 binding) | Antaga,b | PSP | 1% |
| GABAA (agonist binding) | Agonist c,d | MDS | 6% |
| GABAA (responses) | Agonist c,d | AMC | inactivei |
| Kappa opioid | Agonist c,d | PSP | 50% |
| ORL1 | Agonist c,d | MDS | 11% |
| CCK2 (CCKB) | Agonist c | MDS | 0% |
| H1 | Antag a,f | PSP/MDS | 41% / 31% |
| H2 | Antag a,f | MDS | 33% |
| H3 | complexf | LACD | 7.3 ± 0.1 |
| H4 | unknown | LACD | 6.6 ± 0.1 |
| eNOSl | uncertain | MDS | 0% |
| nNOSl | uncertain | MDS | 0% |
| FAAHl | activator | MDS | 8% |
CC12 was screened at the receptors/enzymes shown. For each receptor, column 2 shows the theoretical action on that receptor which would be required to inhibit analgesic activity. For example, CC12 would need to be a μ opioid antagonist in order to block opioid analgesia.
Antagonism at this receptor reduces antinociceptive responses.
Blockade of this receptor blocks excitatory transmission in brain stem antinociceptive circuits (Heinricher et al., 2001b).
Activation of this receptor reduces opioid and, in several cases, cannabinoid antinociception (Zonta et al., 1981; Vaughan et al., 1999; Pan et al., 1997; Heinricher et al., 1997, 2001a).
Activation of this receptor hyperpolarizes “off” cells in the rostral ventral medulla (Pan et al., 1997; Heinricher et al., 1997).
Activation of NT1 stimulates RVM “on” cell firing, facilitating nociception (Neubert et al., 2004)
Activation of this receptor can have opposing actions on nociceptive assays depending on agonist dose, route, CNS region and/or nociceptive test.
Values are mean ± SEM for 3 experiments performed in triplicate (for pA2 values) or mean percent inhibition of binding (10 μM) in triplicates from a single experiment.
Assays performed as described in Methods at Albany Medical College (AMC), Leiden Amsterdam Center for Drug Design (LACD), NIMH Psychopharmacology Screening Program (PSP), the same program's high throughput screening program (PSP-HTS), or MDS Pharma Services (MDS).
CC12 (up to 500 μM) did not display any GABAA agonist properties when tested exactly as described previously (Cannon et al., 2004) in HEK293 cells expressing recombinant α1β2χ2 receptors (n=12).
Inactive as agonist, antagonist or allosteric modulator at 10 μM.
CC12 (10 μM) was also inactive at NK2, NK3, vassopressin V1 and V2, and oxytocin receptors by the same methods.
Abbreviations: eNOS, nNOS: endothelial and neuronal forms of nitric oxide synthase; FAAH: fatty acid amide hydrolase.