- 1-[2-methoxy-5-(3-phenylpropyl)]-2-aminopropane unexpectedly shows 5-HT2A serotonin receptor affinity and antagonist character
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Certain phenylethylamines, such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a), are high-affinity 5-HT2 agonists. Previous structure - affinity studies have concluded that both the 2,5-dimethoxy substitution pattern and the nature of substituents at the 4-position are important determinants of high affinity. We recently demonstrated that replacement of the bromo group of DOB with a 3-(phenyl)propyl substituent results in retention of affinity and that, counter to established structure - affinity relationships, the 2,5-dimethoxy substitution pattern is no longer a requirement for the binding. The present investigation extends these findings by examining a series of analogues, 3, lacking a 5-methoxy group. It was additionally found that shifting the phenylalkyl substituent from the 4- to the 5-position (e.g., 4i) also results in retention of affinity. For example, 1-(2-methoxy-5-(3-phenylpropyl)-2-aminopropane (6; the α-methyl derivative of 4i) binds at 5-HT2A receptors with high affinity (Ki = 13 nM) and possesses 5-HT2A antagonist character. Thus, not only is the 2,5-dimethoxy substitution pattern not a requirement for the binding of certain phenylethylamines at 5-HT2A receptors, the presence of a 4-position substituent (previously thought to serve as a modulator of affinity of DOB-like agents) is also not required. Striking differences in the 5-HT2A binding requirements of the present compounds as compared to DOB-like agents suggest multiple substituent-dependent modes of binding.
- Rangisetty,Dukat,Dowd,Herrick-Davis,DuPre,Gadepalli,Teitler,Kelley,Sharif,Glennon
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p. 3283 - 3291
(2007/10/03)
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- Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine σ ligands as potential antipsychotic drugs
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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 σ 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,Y-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 σ 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, Atsuro,Ohta, Kohmei,Sekiguchi, Yoshinori,Okuyama, Shigeru,Chaki, Shigeyuki,Kawashima, Yutaka,Hatayama, Katsuo
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p. 1076 - 1087
(2007/10/03)
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- Alkoxyphenylalkylamine derivatives
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An alkoxyphenylalkylamine derivative represented by the following formula: STR1 (wherein X1 and X2 may be either the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy g
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