We characterized the histamine H1 receptor agonism of various histaprodifen derivatives in guinea pig isolated ileum and trachea in comparison with histamine. Based on their affinity (calculated pKA values for ileum and trachea, respectively), the compounds were ranked as follows: suprahistaprodifen (8.31/8.08) > Nα-(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) ≧ Nα-(4-phenylbutyl)histaprodifen (0.083/1.54). In the ileum, histamine and methylhistaprodifen showed a high histamine H1 receptor reserve while suprahistaprodifen and Nα-(4-phen-ylbutyl)histaprodifen are devoid of any histamine H1 receptor reserve. On the trachea, no histamine H1 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 Nα-(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 pA2 (7.60–8.29) and/or pD′2 values (6.28–7.90) depending on the tissue and/or the agonist are discussed.

Keywords:
Histaprodifen derivatives, Levocetirizine, Histamine H1 receptor antagonism, Receptor reserve, Ileum, guinea pig, Trachea, guinea pig
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© 2007 S. Karger AG, Basel
2006
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