Design, Synthesis, Structure−Activity Relationships, and Biological Characterization of Novel Arylalkoxyphenylalkylamine σ Ligands as Potential Antipsychotic Drugs

Abstract

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.

Sigma receptors: Potential targets for a new class of antidepressant drug

“… [10] Nakazato, A., K, Ohta et al, (1999) “Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine sigma ligands as potential antipsychotic drugs. J Med Chem 42 (6): 1076–1087.…”

Early Development of Sigma-Receptor Ligands

“…A diverse chemical structural class of compounds with good affinity to s receptors was reported, which included haloperidol (13) [70] phenylalkylpiperazine (14) [71], phenylalkylpiperidine (15) [71], octahydrobenzo[f ] quinoline (16) [72], BD1008 (17) [73] and alkylamines (18) [74] as shown in FiguRe 4. As s receptors bind to compounds with diverse structures it was assumed that s receptors might have good flexibility at the active site, or, alternatively, these diverse agents might be sharing some common features.…”

Synthesis and SAR of 1-Alkyl-2-phenylethylamine Derivatives Designed fromN,N-Dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine To Discover σ1Ligands

“…To obtain compound 8, compound 11 16 is treated with allylmagnesium bromide followed by hydrogenation of the two allyl groups to afford the desired compound. Direct reaction of propylmagnesium bromide with compound 11 did not yield compound 8 (Scheme 2).…”