M4 agonists/5HT7 antagonists with potential as antischizophrenic drugs: serominic compounds.
Chronic low-dose treatment of rats with the psychomimetic drug, phencyclidine, induces regionally specific metabolic and neurochemical changes in the CNS that mirror those observed in the brains of schizophrenic patients. Recent evidence suggests that drugs targeting serotoninergic and muscarinic receptors, and in particular 5-HT(7) antagonists and M(4) agonists, exert beneficial effects in this model of schizophrenia. Compounds that display this combined pattern of activity we refer to as serominic compounds. Based upon leads from natural product screening, we have designed and synthesised such serominic compounds, which are principally arylamidine derivatives of tetrahydroisoquinolines, and shown that they have the required serominic profile in ligand binding assays and show potential antipsychotic activity in functional assays.
Suckling
Colin J
CJ
Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, UK. c.j.suckling@strath.ac.uk
Murphy
John A
JA
Khalaf
Abedawn I
AI
Zhou
Sheng-ze
SZ
Lizos
Dimitris E
DE
van Nhien
Albert Nguyen
AN
Yasumatsu
Hiroshi
H
McVie
Allan
A
Young
Louise C
LC
McCraw
Corinna
C
Waterman
Peter G
PG
Morris
Brian J
BJ
Pratt
Judith A
JA
Harvey
Alan L
AL
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000737:chemistry*; D012559:Schizophrenia / Q000188:drug therapy*
D014150:Antipsychotic Agents; D018721:Muscarinic Agonists; D043588:Receptor, Muscarinic M4; D001285:Atropine; D000661:Amphetamine