Histaprodifens:  Synthesis, Pharmacological in Vitro Evaluation, and Molecular Modeling of a New Class of Highly Active and Selective Histamine H₁-Receptor Agonists

Abstract

A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H1-Receptor

“…H 1 R agonists are divided into three classes ( Fig. 1): 1) small agonists (2-4) derived from histamine (1), 2) histamine derivatives with bulkier aromatic substituents at position 2 of the imidazole ring (5-18), and 3) histaprodifens, e.g., compounds 19 to 23 Zingel et al, 1995;Elz et al, 2000). H 1 R agonists are important experimental tools to analyze H 1 R function in cellular and organ systems (Zingel et al, 1995;Hill et al, 1997).…”

“…In fact, the K d values of [ 3 H]mepyramine for H 1 Rs from various species differ by ϳ2 to 6-fold (Chang et al, 1979). Moreover, histaprodifens exhibit different potencies and efficacies in the guinea pig ileum and rat aorta (Elz et al, 2000). Furthermore, 2-(3-chlorophenyl)histamine (12) is a potent H 1 R agonist in the guinea pig ileum but failed to exhibit agonistic activity in H 1 R-expressing dibutyryl cAMP-differentiated human HL-60 leukemia cells (Seifert et al, 1994).…”

“…3). Mutagenesis data (Leurs et al, , 1995Ohta et al, 1994;Nonaka et al, 1998) and modeling approaches (Elz et al, 2000) indicated that histamine and histaprodifens interact with amino acid residues in TMs III, IV, V, and VII. Considering the alignment of H 1 Rs with bovine rhodopsin (Palczewski et al, 2000) and results of the substituted-cysteine accessibility method with the dopamine D 2 -receptor (Ballesteros et al, 2001), there are no amino acid differences in the ligand binding pocket of gpH 1 R and hH 1 R. The two lipid-directed residues, Phe-153 in TM IV of hH 1 R versus Leu in gpH 1 R and Ile-433 in TM VI of hH 1 R versus Val in gpH 1 R, represent the only differences near the binding site.…”

Ligand-Specific Contribution of the N Terminus and E2-Loop to Pharmacological Properties of the Histamine H1-Receptor

“…A Rotiszint ecoplus (Roth, Karlsruhe, Germany) liquid scintillation cocktail was used. Histaprodifens were synthesized as described by Elz et al (2000), Menghin et al (2003), andStriegl (2006). Construction of pGEMh gpE2 H 1 R, pGEMh gpNgpE2 H 1 R, pVLh gpE2 H 1 R, and pVLh gpNgpE2 H 1 R. First, a pGEM-3Z-SFh gpN H 1 R plasmid was constructed.…”

“…1), identified as potent H 1 R agonists at the guinea pig (gp) ileum (Elz et al, 2000;Menghin et al, 2003), a 3,3-diphenylpropyl moiety is combined with a 2-substituted histamine. A pharmacological characterization of histaprodifens at the human H 1 R (hH 1 R) and guinea pig H 1 R (gpH 1 R) showed significant species differences Straßer et al, 2008).…”