Identification of 4-(1H-Imidazol-4(5)-ylmethyl)pyridine (Immethridine) as a Novel, Potent, and Highly Selective Histamine H₃Receptor Agonist

Abstract

In this study, the piperidine ring of immepip and its analogues was replaced by a rigid heterocyclic pyridine ring. Many compounds in the series exhibit high affinity and agonist activity at the human histamine H(3) receptor. Particularly, the 4-pyridinyl analogue of immepip (1c, immethridine) is identified as a novel potent and highly selective histamine H(3) receptor agonist (pK(i) = 9.07, pEC(50) = 9.74) with a 300-fold selectivity over the closely related H(4) receptor.

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

“…At the hH 4 R these ligands also act as agonists, but exert somewhat lower intrinsic activity (␣ values of 0.9, 0.9, and 0.6, respectively) ( Table 3). 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).…”

“…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

“…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). Other H 3 receptor agonists have been described with novel structural variations, including immethridine (human H 3 receptor K i = 0.9 nM, 90% agonist efficacy), an analog of immepip wherein the highly basic piperidine moiety is replaced by a less basic pyridinyl moiety (Kitbunnadaj et al, 2004). A particularly interesting ligand is the "protean" (Kenakin, 2002) agonist proxyfan (38) (Gbahou et al, 2003), a compound that does not fit neatly into a rigid categorization of agonist or antagonist, because its properties have been found to depend on the system assessing efficacy, with full agonism, neutral antagonism, and inverse agonism seen.…”

Effects of Histamine H₄ Receptor Ligands in a Mouse Model of Gastric Ulceration

“…Since it is well documented that H 3 Rs are involved in histamine-mediated gastric protection in rats [for review, see [38]], it is conceivable to hypothesize that putative damaging effects of H 4 R agonists could be masked by H 3 R-mediated gastroprotective activity. However, unpublished data from our group showed that the highly selective H 3 R agonist immethridine [39] was not protective against the IND+BET-induced gastric damage in mice. Previous data in rats showed that both VUF8430 and VUF10460 significantly aggravated the ulcerogenic effect of 0.6 N HCl [32], thus suggesting that species (mouse vs. rat) and/or the type of ulcerogenic stimulus (IND vs. 0.6 N HCl) may be the key factor responsible for the lack of effects of H 4 R agonists observed in the present experiments.…”