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 h aloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy-6H -dibenzo[b,d]pyran hydrochloride 2a had selective affinity for a receptor o ver dopamine D-2 receptor; This compound was designed to eliminate two bond s of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH2O- band to maintain the planar s tructure. In light of the evidence, N,N-dipropyl-2-(4-methoxy-3-benzyloxylp henyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eli minated 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. T he chemical modification of compound 10b led to the discovery that N,N-dipr opyl-2-[4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (N E- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for a receptor and had a potent activity in an animal model when the drug was given orally. We report here the desig n, synthesis, structure-activity relationships, and biological characteriza tion of novel arylalkoxyphenylalkylamine derivatives 3.