Huang Y, Luedtke R R, Freeman R A, Wu L, Mach R H
Department of Radiology-PET Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
J Med Chem. 2001 May 24;44(11):1815-26. doi: 10.1021/jm0100077.
A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D2 and D3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1-alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides (1-6), (S)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19-25), (R)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo[3.3.1]nonan-3beta-yl)-4-bromo-1-methoxy-2-naphthamides (32, 33). The results of in vitro radioligand binding studies indicated that the majority of the naphthamide analogues bound with high affinity at both the D2 and D3 dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D3 dopamine receptor subtype. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects the binding affinity at D2 and D3 dopamine receptors. The bulkiness of the N-(1-alkyl) substituent was found to (a) have no effect on pharmacologic selectivity, (b) increase the affinity at D3 receptors, or (c) decrease the affinity at D2 receptors. The most potent analogue in this series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilibrium dissociation (K(i)) values of 1.8 and 0.2 nM for D2 and D3 receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K(i) values of 62.8 and 2.4 nM for D2 and D3 receptors, respectively. Radioligand binding results for sigma receptors indicated that the structure of the amine moiety and the N-(1-alkyl) substitutions also significantly influence the affinity and selectivity of these compounds at the sigma1 and sigma2 sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3beta-yl central ring were found to be selective for sigma2 receptors.
合成了一系列萘酰胺，并使用放射性配体结合技术测定了这些化合物对多巴胺D2和D3受体的亲和力。所制备的萘酰胺化合物包括N-(1-烷基哌啶-4-基)-4-溴-1-甲氧基-2-萘酰胺(1-6)、(S)-N-(1-烷基吡咯烷-3-基)-4-溴-1-甲氧基-2-萘酰胺(7-12)、(R)-N-(1-烷基吡咯烷-3-基)-4-溴-1-甲氧基-2-萘酰胺(13-18)、(S)-N-(1-烷基-2-吡咯烷基甲基)-4-溴-1-甲氧基-2-萘酰胺(19-25)、(R)-N-(1-烷基-2-吡咯烷基甲基)-4-溴-1-甲氧基-2-萘酰胺(26-31)以及N-(9-烷基-9-氮杂双环[3.3.1]壬烷-3β-基)-4-溴-1-甲氧基-2-萘酰胺(32、33)。体外放射性配体结合研究结果表明，大多数萘酰胺类似物在多巴胺D2和D3受体亚型上均具有高亲和力结合，并且大多数化合物对多巴胺D3受体亚型表现出一定的选择性。这些结果表明，中心胺部分(哌啶、吡咯烷和9-氮杂双环[3.3.1]壬烷)环的结构以及胺上的N-(烷基)取代对D2和D3多巴胺受体的结合亲和力有显著影响。发现N-(1-烷基)取代基的体积大小(a)对药理选择性无影响，(b)增加对D3受体的亲和力，或(c)降低对D2受体的亲和力。该系列中最有效的类似物是(S)-N-(1-环庚基吡咯烷-3-基)-4-溴-1-甲氧基-2-萘酰胺(10)，其对D2和D3受体的平衡解离(K(i))值分别为1.8和0.2 nM。最具选择性的类似物是(R)-N-(1-环庚基-2-吡咯烷基甲基)-4-溴-1-甲氧基-2-萘酰胺(30)，其对D2和D3受体的K(i)值分别为62.8和2.4 nM。σ受体的放射性配体结合结果表明，胺部分的结构和N-(1-烷基)取代也显著影响这些化合物在σ1和σ2σ受体亚型上的亲和力和选择性。发现含有9-氮杂双环[3.3.1]壬烷-3β-基中心环的两种萘酰胺对σ2受体具有选择性。
