Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine sigma ligands as potential antipsychotic drugs.
sigma Receptor antagonists may be effective antipsychotic drugs that do not induce motor side effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy-6H-dibenzo[b,d]pyran hydrochloride 2a had selective affinity for sigma receptor over dopamine D2 receptor. This compound was designed to eliminate two bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH2O- bond to maintain the planar structure. In light of the evidence, N, N-dipropyl-2-(4-methoxy-3-benzyloxylphenyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran derivative 2a, it might be more released from the rigid structure of apomorphine 1 than compound 2a. The chemical modification of compound 10b led to the discovery that N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for sigma receptor and had a potent activity in an animal model when the drug was given orally. We report here the design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine derivatives 3.
Nakazato
A
A
Medicinal and Pharmaceutical Research Laboratories, Taisho Pharmaceutical Company, Ltd., 1-403 Yoshino-cho, Ohmiya, Saitama 330-8530, Japan. s10968@ccm.taisho.co.jp
Ohta
K
K
Sekiguchi
Y
Y
Okuyama
S
S
Chaki
S
S
Kawashima
Y
Y
Hatayama
K
K
D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011437:Propylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
D000840:Anisoles; D014150:Antipsychotic Agents; D008024:Ligands; D011437:Propylamines; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride