Abstract
We characterized the histamine H<sub>1</sub> receptor agonism of various histaprodifen derivatives in guinea pig isolated ileum and trachea in comparison with histamine. Based on their affinity (calculated pK<sub>A</sub> values for ileum and trachea, respectively), the compounds were ranked as follows: suprahistaprodifen (8.31/8.08) > N<sup>α</sup>-(4-phenylbutyl)histaprodifen (7.22/5.93) ≧ histamine (5.79/5.19) ≈ methylhistaprodifen (5.57/6.07). Based on their efficacy (calculated τ values for ileum and trachea, respectively), the compounds were ranked as follows: methylhistaprodifen (37.67/2.50) > histamine (5.64/1.80) > suprahistaprodifen (1.63/1.42) ≧ N<sup>α</sup>-(4-phenylbutyl)histaprodifen (0.083/1.54). In the ileum, histamine and methylhistaprodifen showed a high histamine H<sub>1</sub> receptor reserve while suprahistaprodifen and N<sup>α</sup>-(4-phen-ylbutyl)histaprodifen are devoid of any histamine H<sub>1 </sub>receptor reserve. On the trachea, no histamine H<sub>1 </sub>receptor reserve was demonstrable with the four tested agonists. The kinetic of contraction/relaxation of the ileum was faster with histamine and methylhistaprodifen than with suprahistaprodifen and N<sup>α</sup>-(4-phenylbutyl)histaprodifen. Histamine contracted the trachea faster than histaprodifen derivatives. Levocetirizine antagonized contractions induced by histamine and histaprodifen derivatives in both tissues. The differences observed in the calculated pA<sub>2</sub> (7.60–8.29) and/or pD′<sub>2</sub> values (6.28–7.90) depending on the tissue and/or the agonist are discussed.
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