4-Hydroxypiperidines and Their Flexible 3-(Amino)propyloxy Analogues as Non-Imidazole Histamine H3 Receptor Antagonist: Further Structure–Activity Relationship Exploration and In Vitro and In Vivo Pharmacological Evaluation

Abstract

Presynaptic histamine H3 receptors (H3R) act as auto- or heteroreceptors controlling, respectively, the release of histamine and of other neurotransmitters in the central nervous system (CNS). The extracellular levels of several neurotransmitters are enhanced by H3R antagonists, and there is a great interest for potent, brain-penetrating H3 receptor antagonists/inverse agonists to compensate for the neurotransmitter deficits present in various neurological disorders. We have shown that 1-[(benzylfuran-2-yl)methyl]piperidinyl-4-oxyl- and benzyl- derivatives of N-propylpentan-1-amines exhibit high in vitro potencies toward the guinea pig H3 receptor (jejunum), with pA2 = 8.47 and 7.79, respectively (the reference compound used was thioperamide with pA2 = 8.67). Furthermore, following the replacement of 4-hydroxypiperidine with a 3-(methylamino)propyloxy chain, the pA2 value for the first group decreased, whereas it increased for the second group. Here, we present data on the impact of elongating the aliphatic chain between the nitrogen of 4-hydroxypiperidine or 3-(methylamino)propan-1-ol and the lipophilic residue. Additionally, the most active compound in this series of non-imidazole H3 receptor antagonists/inverse agonists, i.e., ADS-003, was evaluated for its affinity to the recombinant rat and human histamine H3 receptors transiently expressed in HEK-293T cells. It was shown that ADS-003, given parenterally for 5 days, reduced the food intake of rats, as well as changed histamine and noradrenaline concentrations in the rats’ brain in a manner and degree similar to the reference H3 antagonist Ciproxifan.

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases

“…In previous studies on 4-hydroxypiperidines, the two ligands ADS003 and ADS009 (Figure ) were shown to be highly potent antagonists/inverse agonists at the H 3 R. They were used as lead compounds for the following structural modification: replacement of the flexible five-methylene group chain with a benzene, biphenyl, or naphthalene linker (Figure ). The idea to replace the flexible alkyl linker with semirigid groups of the lead compounds is consistent with studies that have demonstrated that replacement of the alkyl chain with more rigid moieties results in the formation of higher affinity H 3 R ligands . A moiety with a more restricted conformation may be better fitted to the receptor-binding site due to reduced flexibility (i.e., degrees of freedom) …”

“…Previously, our laboratory has described piperazine, 40 guanidine, 41 and 4-hydroxpiperidine-based H 3 R antagonists. 42,43 The structure−activity relationship (SAR) of the 4- 2). 42,43 Further in vivo evaluation of the impact of ADS003 on brain neurotransmitter systems showed its ability to cross the blood−brain barrier and potency at H 3 R similar to the reference compound, ciproxifan.…”

“…Previously, our laboratory has described piperazine, guanidine, and 4-hydroxpiperidine-based H 3 R antagonists. , The structure–activity relationship (SAR) of the 4-hydroxpiperidine series found the most potent compounds to be 5-((1-(benzofuran-2-ylmethyl)­piperidin-4-yl)­oxy)- N -methyl- N -propylpentan-1-amine ( ADS003 ) (pA 2 = 8.47, for reference: thioperamide pA 2 = 8.67) and 5-((1-benzylpiperidin-4-yl)­oxy)- N -methyl- N -propylpentan-1-amine ( ADS009 ) (pA 2 = 7.79) (Figure ). , Further in vivo evaluation of the impact of ADS003 on brain neurotransmitter systems showed its ability to cross the blood–brain barrier and potency at H 3 R similar to the reference compound, ciproxifan …”

Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists

“… 33 Previous studies have demonstrated that replacement of the alkyl chain with more rigid moieties such as aryl or heterocyclic rings results in the formation of highly affine H 3 R ligands. 34 Furthermore, a moiety with a more restricted conformation may be better fitted to the receptor-binding site due to reduced flexibility (i.e., degrees of freedom). 28 A key design element was to conserve the number of atoms between the phenoxy moiety and the basic nitrogen of piperazine and maintain an overall reduction in the number of rotatable bonds, thus producing more conformationally restricted compounds.…”

“…The idea of synthesizing compounds in which the flexible alkyl chain was replaced by a semirigid aryl or cycloalkyl ring arose from our previous experiments and literature data . Previous studies have demonstrated that replacement of the alkyl chain with more rigid moieties such as aryl or heterocyclic rings results in the formation of highly affine H 3 R ligands . Furthermore, a moiety with a more restricted conformation may be better fitted to the receptor-binding site due to reduced flexibility (i.e., degrees of freedom) .…”