Structural modifications in the distal, regulatory region of histamine H3 receptor antagonists leading to the identification of a potent anti-obesity agent

DOI: 10.1016/j.ejmech.2020.113041

Source and publish data:

European Journal of Medicinal Chemistry (2021)

Update date:2022-08-04

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Authors:

Szczepańska, Katarzyna

Pockes, Steffen

Podlewska, Sabina

H?ring, Carina

Mika, Kamil

Latacz, Gniewomir

Bednarski, Marek

Siwek, Agata

Karcz, Tadeusz

Nagl, Martin

Bresinsky, Merlin

M?nnich, Denise

Seibel, Ulla

Kuder, Kamil J.

Kotańska, Magdalena

Stark, Holger

Elz, Sigurd

Kie?-Kononowicz, Katarzyna

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Article abstract of DOI:10.1016/j.ejmech.2020.113041

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H₃ receptor (H₃R) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the H₃R appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on H₃R affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the H₃R (K_i = 3.17 and 7.70 nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H₃ receptor. While its structural replacement to piperidine is also tolerated for H₃R binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the H₃R, as well as drug-like properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test results of compound 9 (structural analogue of Abbott's A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound.

Full text of DOI:10.1016/j.ejmech.2020.113041

European Journal of Medicinal Chemistry xxx (xxxx) xxx

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Research paper

Structural modiﬁcations in the distal, regulatory region of histamine

H₃receptor antagonists leading to the identiﬁcation of a potent anti-

obesity agent

Katarzyna Szczepanska , Steffen Pockes ^*, Sabina Podlewska ^a, Carina Horing ,

ꢀ

€

Kamil Mika ^d, Gniewomir Latacz ^a, Marek Bednarski ^d, Agata Siwek ^e, Tadeusz Karcz ^a,

Martin Nagl , Merlin Bresinsky , Denise Monnich , Ulla Seibel , Kamil J. Kuder ,

Magdalena Kotanska , Holger Stark , Sigurd Elz , Katarzyna Kiec-Kononowicz

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow, 30-688, Poland

Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitatsstraße 31, D-93053, Regensburg, Germany

Maj Institute of Pharmacology, Polish Academy of Sciences, Sme˛tna 12, Krakow, 31-343, Poland

Department of Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow, 30-688,

€

a, **

ꢀ

€

ꢀ

Poland

ꢀ

Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow, 30-688, Poland

^fInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225, Duesseldorf, Germany

a r t i c l e i n f o

a b s t r a c t

Article history:

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be

potent histamine H₃receptor (H₃R) ligands in the nanomolar concentration range. The most inﬂuential

modiﬁcation that affected the afﬁnity toward the H₃R appeared by introducing electron-withdrawing

moieties into the distal aromatic ring. In order to ﬁnally discuss the inﬂuence of the characteristic 4-

pyridylpiperazine moiety on H₃R afﬁnity, two Ciproxifan analogues 2 and 3 with a slight modiﬁcation

in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led

to slightly reduced afﬁnity towards the H₃R (K_i¼ 3.17 and 7.70 nM, respectively). In fact, 3 showed the

highest antagonistic properties among all compounds in this series, hence afﬁrming our previous as-

sumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the

human histamine H₃receptor. While its structural replacement to piperidine is also tolerated for H₃R

binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interac-

tion. The putative protein-ligand interactions responsible for their high afﬁnity were demonstrated using

molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the H₃R, as well as drug-like

properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test

results of compound 9 (structural analogue of Abbott’s A-331440) clearly indicate that it may affect the

amount of calories consumed, thus act as an anorectic compound.

Received 28 August 2020

Received in revised form

7 November 2020

Accepted 16 November 2020

Available online xxx

Keywords:

Histamine H₃receptor

Non-imidazole histamine H₃R ligands

Piperazine derivatives, Selective ligands

Molecular docking

Anti-obesity agents

1. Introduction

hand, as postsynaptic H₃heteroreceptors they also modulate the

release of other neurotransmitters such as dopamine, acetyl-

The histamine H₃receptor (H₃R) has been pharmacologically

discovered in 1983 as presynaptic autoreceptor [1] involved in a

negative feedback modulation of histamine synthesis and inhi-

bition of its release from histaminergic neurons [1]. On the other

choline, serotonin, norepinephrine, g-aminobutyric acid, gluta-

mate, substance P [2e4]. The H₃R is expressed predominantly in

the central nervous system (CNS), especially in the regions

associated with cognition, sleep, wakefulness and homeostatic

regulation [5]. Regarding the distribution of the H₃R in the body

combined with its regulatory impact on essential neurotrans-

mitters, H₃R-inhibiting compounds (antagonists/inverse ago-

nists) represent a highly attractive class of ligands in the search

for new drugs.

* Corresponding author.

** Corresponding author.

E-mail addresses: steffen.pockes@ur.de (S. Pockes), mfkonono@cyf-kr.edu.pl

ꢀ

(K. Kiec-Kononowicz).

https://doi.org/10.1016/j.ejmech.2020.1 13041

ꢀ

Please cite this article as: K. Szczepanska, S. Pockes, S. Podlewska et al., Structural modiﬁcations in the distal, regulatory region of histamine H₃

receptor antagonists leading to the identiﬁcation of a potent anti-obesity agent, European Journal of Medicinal Chemistry, https://doi.org/

10.1016/j.ejmech.2020.113041

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European Journal of Medicinal Chemistry, Corrected proof, 113041. doi:10.1016/j.ejmech.2020.113041

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