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IntroductionHistaprodifen derivatives were previously described as a new family of potent and selective histamine H 1 -agonists [1, 2, Menghin S et al., 2002, EHRS, XXX th meeting, abstract book, Poster P65]. The present experiments were designed to further study the histamine H 1 -agonist properties of histamine (HA), methylhistaprodifen (MHP), N a -(2-(1H-imidazol-4-yl)-ethyl)histaprodifen (IEHP) also named suprahistaprodifen and N a -(4-phenylbutyl)histaprodifen (PBHP) on guinea-pig isolated trachea and ileum, preparations that are characterised by a low or high histamine H 1 receptor reserve, respectively [3]. Materials and methodsStrips of ileum or tracheal rings were isolated from male Dunkin-Hartley guinea-pigs (250 -350 g, used under guidelines approved by the UCB Pharma Ethical Committee) and mounted in organ baths (at 1 g resting tension) filled with Tyrode's (ileum) or Krebs' (trachea) solution maintained at 37°C and gassed with 95 % O 2 -5 % CO 2 . Isometric contractions were measured by force-displacement transducers coupled to a computer system (EMKA Technologies, Paris, France) capable of controlling (i) automatic data acquisition, (ii) bath washout by automatic fluid circulation through electrovalves at predetermined times, and (iii) automatic dilution/injection of drug in the bath at predetermined times or signal stability. Concentration-response curves to HA, MHP, IEHP, or PBHP were non-cumulatively (ileum) or cumulatively (trachea) elicited as described by Van Rossum et al. [4]. Histamine and components of physiological saline solutions were purchased from Sigma (St. Louis, MO, USA). MHP, IEHP and PBHP were synthesised at the Free University of Berlin (Germany). Results and discussionOn guinea-pig isolated trachea and ileum, HA, MHP, IEHP or PBHP (Fig. 1) induced a concentration-dependent contraction of the tissues. On both tissues, HA (data not shown) showed a faster onset and offset of action than MHP, IEHP or PBHP. Histamine H 1 -agonists (Table 1) were usually less potent on guinea-pig isolated trachea than on the isolated ileum. However, this difference of potency depended on the agonist used with HA or PBHP being about 20 fold less potent on trachea than on ileum, MHP only 2.5 fold less potent on trachea than on ileum and IEHP equipotent on both tissues. Unlike HA, MHP and IEHP, where a similar intrinsic activity was observed on both tissues, the intrinsic activity of PBHP was higher on guinea-pig isolated trachea than on the ileum. The potency of an agonist reflects both the ability of the drug to bind to its receptor (affinity) and the ability of the drug to induce a response once it is bound (efficacy), defining two types of agonist [5]. An 'efficacy-driven' agonist has high efficacy (a maximal response with a small number of receptors occupied). A change in the receptor number or receptor-coupling efficiency shifts the concentrationresponse curve to the right but does not influence the maximum of the curve. In contrast an 'affinity-driven' agonist may have the same potency in a high...

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 pK_A values for ileum and trachea, respectively), the compounds were ranked as follows: suprahistaprodifen (8.31/8.08) > N^α-(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^α-(4-phenylbutyl)histaprodifen (0.083/1.54). In the ileum, histamine and methylhistaprodifen showed a high histamine H₁ receptor reserve while suprahistaprodifen and N^α-(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 N^α-(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.