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

Abstract

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, Mr = 483.42, monoclinic, C2/c, a = 21.916 (4), b = 15.207 (2), c = 14.052 (2) Å, β = 101.56 (1)°, V = 4588 (1) Å3, Z = 8, Dx = 1.40 Mg m−3, λ(Mo Kα) = 0.71069 Å, μ = 1.823 mm−1, F(000) = 2008, T = 295 K, R = 0.035 for 2617 observed reflections; (2) N-phenylimidocarbonimidic diamide (1-phenylbiguanide), C8H11N5, Mr = 177.21, monoclinic, P21/c, a = 9.781 (2), b = 35.040 (5), c = 11.000 (2) Å, β = 97.72 (1)°, V = 3736 (1) Å3, Z = 16, Dx = 1.26 Mg m−3, λ(Mo Kα) = 0.71069 Å, μ= 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), C15H17C12NO2, Mr = 314.21, triclinic, P{\bar 1}, a = 8.480 (3), b = 9.840 (3), c = 10.15 (4) Å, α = 90.04 (3), β = 111.77 (3), γ = 105.07 (3)°, V = 755.6 (5) Å3, Z = 2, Dx = 1.38 Mg m−3, λ(Mo Kα) = 0.71069 Å, μ = 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[cf]pyrizino[1,2-a]azepine hydrochloride (mianserin.HCl), C18H21N2 +.Cl−, Mr = 300.83, monoclinic, P21/a, a = 9.014 (2), b = 14.917 (2), c = 12.412 (2) Å, β = 108.84 (1)°, V = 1579.5 (5) Å3, Z = 4, Dx = 1.26 Mg m−3, λ(Mo Kα) = 0.71069 Å, μ = 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.