N-Substituted Piperidinyl Alkyl Imidazoles:  Discovery of Methimepip as a Potent and Selective Histamine H₃ Receptor Agonist

Abstract

In this study, we continue our efforts toward the development of potent and highly selective histamine H(3) receptor agonists. We introduced various alkyl or aryl alkyl groups on the piperidine nitrogen of the known H(3)/H(4) agonist immepip and its analogues (1-3a). We observed that N-methyl-substituted immepip (methimepip) exhibits high affinity and agonist activity at the human histamine H(3) receptor (pK(i) = 9.0 and pEC(50) = 9.5) with a 2000-fold selectivity at the human H(3) receptor over the human H(4) receptor and more than a 10000-fold selectivity over the human histamine H(1) and H(2) receptors. Methimepip was also very effective as an H(3) receptor agonist at the guinea pig ileum (pD(2) = 8.26). Moreover, in vivo microdialysis (in rat brain) showed that methimepip reduces the basal level of brain histamine to about 25% after a 5 mg/kg intraperitoneal administration.

Evaluation of Histamine H1-, H2-, and H3-Receptor Ligands at the Human Histamine H4 Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H4 Receptor Agonist

“…As reported previously (Kitbunnadaj et al, 2004), the recently identified H 3 R agonist immethridine (pK i ϭ 9.1 Ϯ 0.1) binds much less potently to the hH 4 R (pK i ϭ 6.6 Ϯ 0.1) and is also not able to fully activate the H 4 R (Table 3). In agreement with our findings with N ␣ -methylhistamine, the methylated immepip analog methimepip shows a large selectivity for the hH 3 R (pK i ϭ 9.0 Ϯ 0.1) over the hH 4 R (pK i ϭ 5.7 Ϯ 0.1), as reported previously (Kitbunnadaj et al, 2005). Also various H 3 R antagonists bind to the hH 4 R (Oda et al, 2000;Liu et al, 2001a;Morse et al, 2001;Zhu et al, 2001).…”

“…Based upon our data, many imidazol-containing H 3 R ligands, including various H 3 R reference compounds, show potent H 4 R activities and should be treated with caution. More recently developed H 3 R agonists, such as immethridine (Kitbunnadaj et al, 2004) or methimmepip (Kitbunnadaj et al, 2005), or nonimidazole H 3 R antagonists, such as JNJ 6379490 (Ling et al, 2004) or A-349821 (Esbenshade et al, 2004), hardly act at the H 4 R and will therefore provide good tools to selectively target the H 3 R. In the series of tested H 3 R ligands, we have identified iodophenpropit as potent neutral H 4 R antagonist and the burimamide analog VUF 4742 as the second identified H 4 R inverse agonist. From the screening of H 2 R ligands, we have identified 4-methylhistamine as the first high-affinity H 4 R agonist (K i ϭ 50 nM) that has a Ͼ100-fold selectivity for the hH 4 R over the other histamine receptor subtypes.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Importantly, methimmepip profoundly reduced CNS microdialysate histamine levels at low doses (5 mg/kg i.p.) (Kitbunnadaj et al, 2005). Other lipophilic agonists have also been described in an extensive SAR study (Govoni et al, 2006), and an agonist (37) (human H 3 receptor K i = 0.17 nM, 77% efficacy) was active in vivo in mice in blocking aggression and stress (Ishikawa et al, 2010).…”

Natriuretic Peptide-Induced Catecholamine Release from Cardiac Sympathetic Neurons: Inhibition by Histamine H3 and H4 Receptor Activation

“…The differentiating protocol involved plating PC12 and PC12-H 3 cells on tissue culture plates coated with collagen (rat tail type VII; SigmaAldrich, St. Louis, MO) combined with exposure to low serum medium containing 1% fetal bovine serum, 0.5% donor horse serum, 1% L-glutamine, and antibiotics supplemented with 7S-NGF (BD Biosciences Discovery Labware, Bedford, MA). For each experiment, the culture medium was aspirated and cells were washed twice with Na-Ringer's (140 mM NaCl, 5 mM KCl, 10 mM HEPES, 1 mM MgCl 2 , 2 mM glucose, and 2 mM CaCl 2 ), then incubated with BNP (100 nM), for 20 min in an incubator at 37°C either in the absence or presence of methimepip (histamine H 3 receptor agonist; 1 nM) (Kitbunnadaj et al, 2005), 4-methylhistamine (histamine H 4 receptor agonist; 20 M) (Lim et al, 2005), 1-{3-[4-(piperidin-1-ylmethyl)phenoxy]propyl}piperidine (JNJ5207852) (histamine H 3 receptor antagonist; 30 nM) (Barbier et al, 2004), or 4-((3R)-3-amino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo [6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine (A943931) (histamine H 4 receptor antagonist; 300 nM) (Cowart et al, 2008). When these drugs were used, PC12-H 3 cells were preincubated with them for 10 min.…”

“…1, A and B). In the presence of the histamine H 3 receptor agonist methimepip (1 nM) (Kitbunnadaj et al, 2005) the K ϩ -induced increase in NE release was reduced by ϳ50%, an effect that was abolished by the selective H 3 receptor antagonist JNJ5207852 (30 nM) (Barbier et al, 2004) (Fig. 1A).…”