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

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-.1/2H(2)O, M(r) = 483.42, monoclinic, C2/c, a = 21.916(4), b = 15.207(2), c = 14.052(2) Angstrom, beta = 101.56(1)degrees, V = 4588(1) Angstrom(3), Z = 8, D-x = 1.40 Mg m(-3), lambda(Mo K alpha) = 0.71069 Angstrom, 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) Angstrom, beta = 97.72(1)degrees, V = 3736(1) Angstrom(3), Z = 16, D-x = 1.26 Mg m(-3), lambda(Mo K alpha) = 0.71069 Angstrom, 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-3-yl 3,5-dichlorobenzoate (MDL 72222), C15H17Cl2NO2, M(r) = 314.21, triclinic, P (1) over bar, a = 8.480(3), b = 9.840(3), c = 10.158(4) Angstrom, alpha = 90.04(3), beta = 111.77(3), gamma = 105.07(3)degrees, V = 755.6(5) Angstrom(3), Z = 2, D-x = 1.38 Mg m(-3), lambda(Mo K alpha) = 0.71069 Angstrom, 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-a]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) Angstrom, beta = 108.84(1)degrees, V = 1579.5(5) Angstrom(3), Z = 4, D-x = 1.26 Mg m(-3), lambda(Mo K alpha) = 0.71069 Angstrom, 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.