We characterized the histamine H(1) receptor agonism of various histaprodifen derivatives in guinea pig isolated ileum and trachea in comparison with histamine. Based on their affinity (calculated pK(A) values for ileum and trachea, respectively), the compounds were ranked as follows: suprahistaprodifen (8.31/8.08) > N(alpha)-(4-phenylbutyl)histaprodifen (7.22/5.93) >or= histamine (5.79/5.19) approximately methylhistaprodifen (5.57/6.07). Based on their efficacy (calculated tau 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) >or= N(alpha)-(4-phenylbutyl)histaprodifen (0.083/1.54). In the ileum, histamine and methylhistaprodifen showed a high histamine H(1) receptor reserve while suprahistaprodifen and N(alpha)-(4-phenylbutyl)histaprodifen are devoid of any histamine H(1 )receptor reserve. On the trachea, no histamine H(1 )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(alpha)-(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(2) (7.60-8.29) and/or pD'(2) values (6.28-7.90) depending on the tissue and/or the agonist are discussed.