Interactions of new and conventional H3-antagonists with non-histaminergic receptors involved in neurogenic and myogenic contractile responses of guinea-pig ileum

1 Possible effects of new and conventional H₃-receptor antagonists towards various non-histaminergic receptors (α₂-adrenergic, 5-HT₃-serotonin, μ-opiate, A₁-adenosine, M₁-and M₃-muscarinic) involved in neurogenic and myogenic contractile responses of guinea-pig ileum are investigated.

2 When the isolated ileum was contracted by the 5-HT₃ receptor agonist, 2-methyl-5-HT (5 × 10⁻⁻⁷–8 × 10⁻⁻⁶ m), acetylcholine (1 × 10⁻⁻⁹–1 × 10⁻⁻⁷ m), KCl (3 × 10⁻⁻² m) or electrical stimulation some of the drugs, included thioperamide and clobenpropit, reduced the contractile response when tested at micromolar concentrations (1–3 × 10⁻⁻⁵ m) (only compound IV exhibited an M₃ competitive antagonism with a pK_B = 5.49 ± 0.18).

3 Ileal twitch responses to electrical stimulation were dose-dependently inhibited by the selective agonists clonidine (3 × 10⁻⁻¹⁰–1 × 10⁻⁻⁷ m), dermorphin (1 × 10⁻⁻¹¹–1 × 10⁻⁻⁸ m), R-N⁶-(2-phenylisopropyl)-adenosine (1 × 10⁻⁻⁹–3 × 10⁻⁻⁸ m) and McN-A-343 (1 × 10⁻⁻⁷–1 × 10⁻⁻⁵ m) with different potencies and comparable efficacy (spike amplitude reduction > 85%). All the H₃ antagonists under study (up to 1 × 10⁻⁻⁵ m) showed no or minor interactions at the neuronal sites except the compound V which behaved as a weak competitive antagonist at α₂-adrenoreceptors (pK_B = 5.96 ± 0.06).

4 In conclusion, both new and conventional H₃-blockers interacted at the enteric neuronal sites here studied with a 1000–30 000 fold lower antagonistic potency than that previously reported for the ileal H₃ histamine receptors. Their spasmolytic activity precludes firm conclusions about the non-competitive interaction with 5-HT₃ ileal receptor which requires further investigations.