Homology modeling inspired synthesis of 5-HT2A receptor inhibitors: A diazepine analogue of the atypical antipsychotic JL13

Enrico Mongeau, Gengyang Yuan, Zachary Minden, Scott Waldron, Raymond Booth, Daniel Felsing, Mary J. Ondrechen, Graham B. Jones

Research output: Contribution to journalLetter

Abstract

Background: The benzoxazepine JL13 is an analogue of the clozapine family of antipsychotic agents which target the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Based on the dearth of clinically effective anti-psychotic agents available, we sought to design and chemically synthesize additional analogues. Methods: Structure function analysis was conducted using state of art computational methods, which were designed to highlight new candidates for chemical synthesis. Efficient syntheses were then conducted and the products screened for affinity to the receptor. Results: Among many new analogues prepared, an aza analogue demonstrated seventeen times greater affinity for the receptor than JL13. Conclusion: An efficient synthetic route to an aza-analogue of JL13 was developed and will allow rapid modifications of the core and synthesis of related libraries.

Original languageEnglish (US)
Pages (from-to)239-244
Number of pages6
JournalCentral Nervous System Agents in Medicinal Chemistry
Volume17
Issue number3
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Receptor, Serotonin, 5-HT2A
Antipsychotic Agents
Clozapine
Libraries
5-(4-methylpiperazin-1-yl)-8-chloropyrido(2,3-b)(1,5)benzoxazepine fumarate

Keywords

  • 5HT receptor
  • Antipsychotic
  • Clozapine
  • Diazepine
  • JL13
  • Synthesis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Neuropsychology and Physiological Psychology
  • Molecular Medicine

Cite this

Homology modeling inspired synthesis of 5-HT2A receptor inhibitors : A diazepine analogue of the atypical antipsychotic JL13. / Mongeau, Enrico; Yuan, Gengyang; Minden, Zachary; Waldron, Scott; Booth, Raymond; Felsing, Daniel; Ondrechen, Mary J.; Jones, Graham B.

In: Central Nervous System Agents in Medicinal Chemistry, Vol. 17, No. 3, 01.01.2017, p. 239-244.

Research output: Contribution to journalLetter

Mongeau, Enrico ; Yuan, Gengyang ; Minden, Zachary ; Waldron, Scott ; Booth, Raymond ; Felsing, Daniel ; Ondrechen, Mary J. ; Jones, Graham B. / Homology modeling inspired synthesis of 5-HT2A receptor inhibitors : A diazepine analogue of the atypical antipsychotic JL13. In: Central Nervous System Agents in Medicinal Chemistry. 2017 ; Vol. 17, No. 3. pp. 239-244.
@article{8cef3c9b3bcd46be8e7a25de38c3bfb7,
title = "Homology modeling inspired synthesis of 5-HT2A receptor inhibitors: A diazepine analogue of the atypical antipsychotic JL13",
abstract = "Background: The benzoxazepine JL13 is an analogue of the clozapine family of antipsychotic agents which target the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Based on the dearth of clinically effective anti-psychotic agents available, we sought to design and chemically synthesize additional analogues. Methods: Structure function analysis was conducted using state of art computational methods, which were designed to highlight new candidates for chemical synthesis. Efficient syntheses were then conducted and the products screened for affinity to the receptor. Results: Among many new analogues prepared, an aza analogue demonstrated seventeen times greater affinity for the receptor than JL13. Conclusion: An efficient synthetic route to an aza-analogue of JL13 was developed and will allow rapid modifications of the core and synthesis of related libraries.",
keywords = "5HT receptor, Antipsychotic, Clozapine, Diazepine, JL13, Synthesis",
author = "Enrico Mongeau and Gengyang Yuan and Zachary Minden and Scott Waldron and Raymond Booth and Daniel Felsing and Ondrechen, {Mary J.} and Jones, {Graham B.}",
year = "2017",
month = "1",
day = "1",
doi = "10.2174/1871524917666170426123607",
language = "English (US)",
volume = "17",
pages = "239--244",
journal = "Central Nervous System Agents in Medicinal Chemistry",
issn = "1871-5249",
publisher = "Bentham Science Publishers B.V.",
number = "3",

}

TY - JOUR

T1 - Homology modeling inspired synthesis of 5-HT2A receptor inhibitors

T2 - A diazepine analogue of the atypical antipsychotic JL13

AU - Mongeau, Enrico

AU - Yuan, Gengyang

AU - Minden, Zachary

AU - Waldron, Scott

AU - Booth, Raymond

AU - Felsing, Daniel

AU - Ondrechen, Mary J.

AU - Jones, Graham B.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: The benzoxazepine JL13 is an analogue of the clozapine family of antipsychotic agents which target the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Based on the dearth of clinically effective anti-psychotic agents available, we sought to design and chemically synthesize additional analogues. Methods: Structure function analysis was conducted using state of art computational methods, which were designed to highlight new candidates for chemical synthesis. Efficient syntheses were then conducted and the products screened for affinity to the receptor. Results: Among many new analogues prepared, an aza analogue demonstrated seventeen times greater affinity for the receptor than JL13. Conclusion: An efficient synthetic route to an aza-analogue of JL13 was developed and will allow rapid modifications of the core and synthesis of related libraries.

AB - Background: The benzoxazepine JL13 is an analogue of the clozapine family of antipsychotic agents which target the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Based on the dearth of clinically effective anti-psychotic agents available, we sought to design and chemically synthesize additional analogues. Methods: Structure function analysis was conducted using state of art computational methods, which were designed to highlight new candidates for chemical synthesis. Efficient syntheses were then conducted and the products screened for affinity to the receptor. Results: Among many new analogues prepared, an aza analogue demonstrated seventeen times greater affinity for the receptor than JL13. Conclusion: An efficient synthetic route to an aza-analogue of JL13 was developed and will allow rapid modifications of the core and synthesis of related libraries.

KW - 5HT receptor

KW - Antipsychotic

KW - Clozapine

KW - Diazepine

KW - JL13

KW - Synthesis

UR - http://www.scopus.com/inward/record.url?scp=85040078717&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040078717&partnerID=8YFLogxK

U2 - 10.2174/1871524917666170426123607

DO - 10.2174/1871524917666170426123607

M3 - Letter

C2 - 28462720

AN - SCOPUS:85040078717

VL - 17

SP - 239

EP - 244

JO - Central Nervous System Agents in Medicinal Chemistry

JF - Central Nervous System Agents in Medicinal Chemistry

SN - 1871-5249

IS - 3

ER -