基于晶体学数据的血清素受体配体的立体化学。NAN-190·HBr、1-苯基双胍、MDL 72222和盐酸米安色林的晶体结构以及对5-HT1、5-HT2和5-HT3受体亚型的选择性标准。
Stereochemistry of serotonin receptor ligands from crystallographic data. Crystal structures of NAN-190.HBr, 1-phenylbiguanide, MDL 72222 and mianserin.HCl and selectivity criteria towards 5-HT1, 5-HT2, and 5-HT3 receptor subtypes.
作者信息
Dalpiaz A, Ferretti V, Gilli P, Bertolasi V
机构信息
Dipartimento di Chimica, Università di Ferrara, Italy.
出版信息
Acta Crystallogr B. 1996 Jun 1;52 ( Pt 3):509-18. doi: 10.1107/s0108768195014765.
The crystal and molecular structures of the following serotoninergic drugs have been determined: (1) 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide hemihydrate (NAN-190.HBr), C23H28N3O3+.Br-.1/2H2O, M(r) = 483.42, monoclinic, C2/c, a = 21.916 (4), b = 15.207 (2), c = 14.052 (2) A, beta = 101.56 (1) degree, V = 4588 (1) A3, Z = 8, Dx = 1.40 Mgm-3, lambda (Mo K alpha) = 0.71069 A, mu = 1.823 mm-1, F(000) = 2008, T = 295 K, R = 0.035 for 2617 observed reflections; (2) N-phenylimidocarbonimidic diamide (1-phenylbiguanide), C8H11N5, M(r) = 177.21, monoclinic, P2(1)/c, a = 9.781 (2), b = 35.040(5), c = 11.000 (2) A, beta = 97.72(1) degree, V = 3736(1)A3, Z = 16, Dx = 1.26 Mg m-3, lambda (Mo K alpha) = 0.71069 A, mu = 0.084 mm-1, F(000) = 1504, T = 295 K, R = 0.070 for 3407 observed reflections; (3) 8-methyl-8-azabicyclo[3.2.1]oct-3yl 3,5-dicholorobenzoate (MDL 72222), C15H17Cl2NO2, M(r) = 314.21, triclinic, P1, alpha = 8.480 (3), b = 9.840 (3), c = 10.158 (4) A, alpha = 90.04 (3), beta = 111.77 (3), gamma = 105.07(3) degrees, V = 755.6(5) A3, Z = 2, Dx = 1.38 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.430 mm-1, F(000) = 328, T = 295 K, R = 0.070 for 1685 observed reflections; (4) 1, 2, 3, 4, 10, 14b-hexahydro-2-methyldibenzo[c.f]pyrizino[1, 2-alpha]azepine hydrochloride (mianserin. HCl), C18H21N2+. Cl-, M(r) = 300.83, monoclinic, P2(1)/a, a = 9.014 (2), b = 14.917 (2), c = 12.412 (2) A, beta = 108.84 (1) degree, V = 1579.5 (5) A3, Z = 4, Dx = 1.26 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.237 mm-1, F(000) = 640, T = 295 K, R = 0.063 for 1493 observed reflections. A systematic structural analysis of the present compounds and others known to interact with the 5-HT1, 5-HT2 and 5-HT3 receptors allows to identify their similarities with the endogenous ligand serotonin (5-HT) and the stereochemical differences which determine selectivity for the various receptor subtypes. The pharmacophoric feature for 5-HT receptor binding is identified in a constant-length vector linking an aromatic ring with a protonated nitrogen, while specific affinities for receptorial subtypes and the nature of the effect appear to be modulated by the dimensions of the substituents at nitrogen.
已测定下列血清素能药物的晶体结构和分子结构
(1) 1-(2-甲氧基苯基)-4-[4-(2-邻苯二甲酰亚氨基)丁基]哌嗪氢溴酸盐半水合物（NAN-190·HBr），C₂₃H₂₈N₃O₃⁺·Br⁻·1/2H₂O，M(r)=483.42，单斜晶系，C2/c，a = 21.916(4)，b = 15.207(2)，c = 14.052(2) Å，β = 101.56(1)°，V = 4588(1) ų，Z = 8，Dx = 1.40 Mg/m³，λ(Mo Kα)=0.71069 Å，μ = 1.823 mm⁻¹，F(000)=2008，T = 295 K，2617个观察反射的R = 0.035；(2) N-苯基异碳亚胺二酰胺（1-苯基双胍），C₈H₁₁N₅，M(r)=177.21，单斜晶系，P2(1)/c，a = 9.781(2)，b = 35.040(5)，c = 11.000(2) Å，β = 97.72(1)°，V = 37,36(1) ų，Z = 16，Dx = 1.26 Mg/m³，λ(Mo Kα)=0.71069 Å，μ = 0.084 mm⁻¹，F(000)=1504，T = 295 K，3407个观察反射的R = 0.070；(3) 8-甲基-8-氮杂双环[3.2.1]辛-3-基3,5-二氯苯甲酸酯（MDL 72222），C₁₅H₁₇Cl₂NO₂，M(r)=314.21，三斜晶系，P1，α = 8.480(3)，b = 9.840(3)，c = 10.158(4) Å，α = 90.04(3)，β = 111.77(3)，γ = 105.07(3)°，V = 755.6(5) ų，Z = 2，Dx = 1.38 Mg/m³，λ(Mo Kα)=0.71069 Å，μ = 0.430 mm⁻¹，F(000)=328，T = 295 K，1685个观察反射的R = 0.070；(4) 1,2,3,4,10,14b-六氢-2-甲基二苯并[c,f]吡嗪并[1,2-α]氮杂卓盐酸盐（米安色林·HCl），C₁₈H₂₁N₂⁺·Cl⁻，M(r)=300.83，单斜晶系，P2(1)/a，a = 9.014(2)，b = 14.917(2)，c = 12.412(2) Å，β = 108.84(1)°，V = 1579.5(5) ų，Z = 4，Dx = 1.26 Mg/m³，λ(Mo Kα)=0.71069 Å，μ = 0.237 mm⁻¹，F(000)=640，T = 295 K，1493个观察反射的R = 0.063。对本化合物及其他已知与5-HT1、5-HT2和5-HT3受体相互作用的化合物进行系统的结构分析，有助于确定它们与内源性配体血清素（5-HT）的相似性以及决定对各种受体亚型选择性的立体化学差异。5-HT受体结合的药效基团特征是在一个将芳香环与质子化氮连接起来的定长向量中确定的，而对受体亚型的特异性亲和力和效应的性质似乎受到氮上取代基尺寸的调节。
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