N-Substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D(2) antagonists/5-HT(1A) partial agonists with potential as atypical antipsychotic agents.
A series of N-substituted 1-(2,3-dihydro-1, 4-benzodioxin-2-yl)methylamine derivatives with D(2) antagonist/5-HT(1A) partial agonist activity has been prepared as potential atypical antipsychotic agents. Optimization of in vitro receptor binding activity and in vivo activity in rodent models of psychosis has led to compound 24, which showed good affinities for human D(2), D(3), and 5-HT(1A) receptors but significantly less affinity for human alpha(1) adrenoceptors and rat H(1) and muscarinic receptors. In rodents, 24 showed functional D(2)-like antagonism and 5-HT(1A) partial agonism. After oral dosing, 24 showed good activity in rodent antipsychotic tests and very little potential to cause extrapyramidal side effects (EPS), as measured by its ability to induce catalepsy in rats only at very high doses. In the light of this promising profile of activity, 24 has been selected for clinical investigation as a novel antipsychotic agent with a predicted low propensity to cause EPS.
Birch
A M
AM
Research and Development Department, Knoll Pharmaceuticals, Pennyfoot Street, Nottingham NG1 1GF, U.K.
Bradley
P A
PA
Gill
J C
JC
Kerrigan
F
F
Needham
P L
PL
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013552:Swine
D014150:Antipsychotic Agents; D004146:Dioxanes; D018492:Dopamine Antagonists; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; C121215:BTS 79018