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Abstract
We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.
Highlights
Histamine (1, Figure 1), a monoamine chemical mediator, acts on four different receptor subtypes, H1, H2, H3, and H4 receptors, which are members of the G protein-coupled receptor superfamily.In early the 1980s, the histamine H3 receptor (H3 R) was identified as a presynaptic autoreceptor in rats [1], and the human H3 R was cloned in 1999 [2]
The backbone conformation is restricted to the develop bioactive ligands, even if the structural information of the target proteins is unknown, trans-configuration, there are two conformers, anti- and syn-form, whose aminoalkyl chains orient to we developed a three-dimensional structural diversity-oriented strategy based on the characteristic the side opposite and same to the cyclopropane ring, respectively, due to the C2–C3 bond rotation structural properties of chiral cyclopropane, which is the rigid and smallest carbocyclic structure [10]
The backbone conformation is restricted to the trans-configuration, there are two conformers, anti- and syn-form, whose aminoalkyl chains orient to the side opposite and same to the cyclopropane ring, respectively, due to the C2–C3 bond rotation (Figure 2a). This bond rotation is limited by the “cyclopropylic strain” that causes a sizable steric repulsion similar to the 1,3-allylic strain between the two adjacent cis-configured substituents, which are fixed in an eclipse orientation on the cyclopropane ring
Summary
Histamine (1, Figure 1), a monoamine chemical mediator, acts on four different receptor subtypes, H1 , H2 , H3 , and H4 receptors, which are members of the G protein-coupled receptor superfamily.In early the 1980s, the histamine H3 receptor (H3 R) was identified as a presynaptic autoreceptor in rats [1], and the human H3 R was cloned in 1999 [2]. The H3 R, which is mainly expressed in the central nervous system (CNS), acts as an autoreceptor to regulate the central levels of histamine and acts as a heteroreceptor to regulate the synthesis and release of other neurotransmitters, such as noradrenaline, acetylcholine, dopamine, and serotonin, and it is involved in various physiological processes, including memory function, cognition, anxiety, pain, food intake, and body temperature regulation. H3 R inhibitors (antagonists/inverse agonists) [3,4,5], and pitolisant (2, Figure 1) was recently authorized in Europe as a medicine for treating narcolepsy with or without cataplexy [6]. Further research is needed to better understand the functions of the histaminergic system in CNS-related disorders and to advance useful H3 antagonists into clinical trials and the market [7]
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