TY - CHAP
T1 - Histamine H3R antagonists
T2 - From scaffold hopping to clinical candidates
AU - Sadek, B.
AU - Łażewska, D.
AU - Hagenow, S.
AU - Kieć-Kononowicz, K.
AU - Stark, H.
N1 - Funding Information:
Support was kindly provided to BS by grants from the United Arab Emirates University, to KK by the Polish National Science Center funds, grants no. 2011/02/A/NZ4/00031 and 2011/01/N/NZ4/01126, and to HS by the European Union-European Cooperation of Science and Technology (EU COST) Actions CM1103, CM1207, and CA15135 as well by DFG INST 208/664-1 FUGG.
Publisher Copyright:
© Springer International Publishing Switzerland 2016.
PY - 2016
Y1 - 2016
N2 - The histamine H3 receptor (H3R), belonging to the family of G-protein-coupled receptors, is predominantly expressed in the central nervous system (CNS). Since its discovery by Arrang et al., it was related to several central nervous system diseases by playing a key role as actuator of neurotransmitter release for, e.g., dopamine, acetylcholine, noradrenaline, or serotonin. Therefore, a huge number of H3R antagonists have been investigated on their potential therapeutic applicability in obesity, depression, mood disorders, neuropathic pain, and sleep– wake disorders (including narcolepsy) as well as cognitive and CNS-linked sensorimotor deficit disorders such as Parkinson’s disease, attention deficit hyperactivity disorder, Alzheimer’s disease, schizophrenia, alcohol addiction, energy homeostasis, epilepsy, obstructive sleep apnea, diabetic neuropathic pain, Tourette’s syndrome, and catalepsy. So far, many structurally diverse H3R antagonists have been synthesized and pharmacologically evaluated. Despite a high diversity of compounds, these structures share a similar construction pattern. The pharmacophore contains a tertiary basic amine (postulated to interact with the conserved aspartate 114 in helix 3), a linker (commonly a linear propyloxy chain or structurally constrained), a central core, and “the eastern” arbitrary region (with high diversity such as second basic, acidic, lipophilic, or polar moieties of different sizes).
AB - The histamine H3 receptor (H3R), belonging to the family of G-protein-coupled receptors, is predominantly expressed in the central nervous system (CNS). Since its discovery by Arrang et al., it was related to several central nervous system diseases by playing a key role as actuator of neurotransmitter release for, e.g., dopamine, acetylcholine, noradrenaline, or serotonin. Therefore, a huge number of H3R antagonists have been investigated on their potential therapeutic applicability in obesity, depression, mood disorders, neuropathic pain, and sleep– wake disorders (including narcolepsy) as well as cognitive and CNS-linked sensorimotor deficit disorders such as Parkinson’s disease, attention deficit hyperactivity disorder, Alzheimer’s disease, schizophrenia, alcohol addiction, energy homeostasis, epilepsy, obstructive sleep apnea, diabetic neuropathic pain, Tourette’s syndrome, and catalepsy. So far, many structurally diverse H3R antagonists have been synthesized and pharmacologically evaluated. Despite a high diversity of compounds, these structures share a similar construction pattern. The pharmacophore contains a tertiary basic amine (postulated to interact with the conserved aspartate 114 in helix 3), a linker (commonly a linear propyloxy chain or structurally constrained), a central core, and “the eastern” arbitrary region (with high diversity such as second basic, acidic, lipophilic, or polar moieties of different sizes).
KW - Antagonists
KW - Clinical candidates
KW - Clinical trials
KW - Cognitive impairments
KW - Drug development
KW - GPCR
KW - Histamine
KW - Inverse agonists
KW - Narcolepsy
KW - Pitolisant
UR - http://www.scopus.com/inward/record.url?scp=85048862140&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048862140&partnerID=8YFLogxK
U2 - 10.1007/978-3-319-40308-3_5
DO - 10.1007/978-3-319-40308-3_5
M3 - Chapter
AN - SCOPUS:85048862140
T3 - Receptors
SP - 109
EP - 155
BT - Receptors
PB - Humana Press Inc.
ER -