Stereochemistry of Serotonin Receptor Ligands from Crystallographic Data. Crystal Structures of NAN-190.HBr, 1-Phenylbiguanide, MDL 72222 and Mianserin.HCI and Selectivity Criteria towards 5-HT_1, 5-HT_2 and 5-HT_3 Receptor Subtypes

摘要

The crystal and molecular structures of the following serotoninergic drugs have been determined: (1) l-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide hemihydrate (NAN-190.HBr), C23H28N3O3+.Br.l/2H2O, Mr = 483.42, monoclinic, C2/c, a = 21.916(4), b = 15.207(2), c = 14.052 (2) A, /3 = 101.56(1)°, V = 4588(1) A3, Z = 8, Dx = 1.40 Mgnr A(Mo Ka) = 0.71069 A, y = 1.823 mm-', F(000) = 2008, T = 295 K, R = 0.035 for 2617 observed reflections; (2) N-phenylimidocarbonimidic diamide (1-phenylbiguanide), CsHnNs, Mr = 177.21, monoclinic, P2i/c, a = 9.781(2), b = 35.040(5), c= 11.000(2)A, p = 97.72(1)°, V = 3736(1)A3, Z = 16, Dx = 1.26Mgm"3, A(Mo Ka) = 0.71069 A, li = 0.084mm-', F(000) = 1504, T = 295K, R = 0.070 for 3407 observed reflections; (3) 8-methyl-8-azabicyclo[3.2.1.]oct-3-yl 3,5-dichlorobenzoate (MDL 72222), C15H17CI2NO2, Mr = 314.21, triclinic, PI, a = 8.480 (3), b = 9.840 (3), c = 10.158 (4) A, a = 90.04 (3), /3 = 111.77(3), 7 = 105.07(3)°, V = 755.6 (5) A3, Z = 2, ?>* = 1.38Mgm-3, A(Mo Ka) = 0.71069A, ju = 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/lpyrizino[l,2-fl]azepine hydrochloride (mianserin.HCl), C18H2iN2+.Cl~, Mr - 300.83, monoclinic, Flla, a = 9.014 (2), b = 14.917 (2), c = 12.412 (2) A, p = 108.84(1)°, V = 1579.5 (5) A3, Z = 4, Dx = 1.26 Mgm"3, A(Mo Ka) = 0.71069 A, yn = 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-HT,, 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.