Table 2.
Inhibition of the polysynaptic reflexes by 5-HT1B agonists
| Inhibition of LPR |
Inhibition of SPR |
|||||
|---|---|---|---|---|---|---|
| Agonist | Antagonist Pretreatment | Receptors That Can Be Activated (Ki < 400 nM) | Efficacy, %change | Potency, −log EC50 | Efficacy, %change | Potency, −log EC50 |
| 5-CT | None | 5-HT1A,1B,1D,2B,5–7 | −96.3 ± 65.4* | 7.08 ± 0.50 | −60.4 ± 77.3* | 7.16 ± 0.51 |
| 5-HT | None | 5-HT1–7 | −78.5 ± 23.2* | 6.56 ± 0.17 | −63.4 ± 43.7* | 6.83 ± 0.43 |
| 5-HT | Methys + gran | 5-HT1B,4 | −84.6 ± 14.7* | 6.47 ± 0.38 | −29.7 ± 23.1*† | 6.26 ± 0.22† |
| 5-HT | RSs | 5-HT1,3–7 | −108.1 ± 28.7* | 6.57 ± 0.23 | −74.3 ± 38.4* | 6.36 ± 0.30 |
| 5-HT | RSs + SB216 | 5-HT1A,1E,1F,3–7 | −52.0 ± 22.0*† | 5.70 ± 0.36† | −59.2 ± 23.65 | 5.86 ± 0.32† |
| α-Methyl-5-HT | None | 5-HT1B,1E,1F,2,4 | −57.3 ± 16.5* | 5.75 ± 0.23 | −64.1 ± 29.4* | 5.86 ± 0.53 |
| BW723C86 | None | 5-HT1B,2,3,6 | −38.0 ± 24.8* | 5.89 ± 0.48 | −49.3 ± 43.2* | 5.92 ± 0.33 |
| EMD386088 | None | 5-HT1B,1D,3,6 | −43.6 ± 35.3* | 5.53 ± 0.35 | −51.2 ± 28.8* | 5.76 ± 0.36 |
| EMD386088 | SB216 + gran | 5-HT6 | 12.4 ± 110.6† | ND | 5.7 ± 43.3† | ND |
| LY344864 | None | 5-HT1F | −57.2 ± 25.4* | 7.12 ± 0.17 | −45.9 ± 26.72* | 7.14 ± 0.21 |
| Methylergonovine | None | 5-HT1E,1F,2 | −40.8 ± 21.3* | 6.47 ± 0.25 | −44.0 ± 25.2* | 6.51 ± 0.15 |
| Zolmitriptan | None | 5-HT1B,1D,1F | −99.5 ± 11.3* | 7.07 ± 0.40 | −55.2 ± 20.6* | 7.08 ± 0.41 |
| Zolmitriptan | SB216 or GR127 | 5-HT1F | −41.2 ± 27.6*† | 5.94 ± 0.25† | −38.2 ± 27.1*† | 6.15 ± 0.70† |
| Zolmitriptan | SB224 | 5-HT1D,1F | −26.6 ± 29.0*† | 5.63 ± 0.53† | −31.5 ± 29.9*† | 5.92 ± 0.57† |
Agonists with varying selectivity for the different 5-HT receptors were applied, sometimes after prior application of 5-HT receptor antagonists to effectively make the agonist action more selective (pretreatment). The receptors that can be activated by this agonist-antagonist combination are indicated (Ki < 400 nM; see details in Table 1). The antagonists used, followed by dose and receptors blocked, were as follows: SB224289 (SB224): 5 μM, 5-HT1B; SB216641 (SB216): 3 μM, 5-HT1B/1D; GR127935 (GR127): 3 μM, 5-HT1B/1D; methysergide (methys): 10 μM, all but 5-HT1B/3/4; granisetron (gran): 0.3 μM, 5-HT3; RS127445: 3 μM, 5-HT2B; and RS102221: 3 μM, 5-HT2C (the latter 2 antagonists were applied together and referred to as RSs). The efficacy of the agonists in inhibiting the long (LPR) and short polysynaptic reflex (SPR) are indicated, normalized by the predrug reflex amplitudes (−100% indicates complete elimination of the excitatory reflex by agonist; < −100% indicates inhibitory reflex emerges with agonist). In addition, the agonists 8-OH-DPAT (5-HT1A/5/7 affinity), LP44 (5-HT7/1A), 2-methyl-5-HT (5-HT2B/3/1F), DOI (5-HT2), cisapride (5-HT4), and MK212 (5-HT2C/3) produced no significant inhibition of the LPR or SPR (not shown, doses ≤30 μM; see text). Data are means ± SD; n > 8 per condition.
P < 0.05, significant change in reflex.
P < 0.05, significant decrease in efficacy or potency after application of antagonists (SB224, SB216, or GR127), relative to the inhibitory action of agonists alone (e.g., zolmitriptan; row above antagonist data).