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−.1/2H2O, 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.

Role of endogenous opioids and serotonin in the hemodynamic response to hemorrhage during hypoxia

Previous studies from our laboratory indicate that acute but not chronic hypoxia decreases the hemorrhage volume required to elicit reflex hypotension. Furthermore, chronically hypoxic animals exhibit an elevated hypotensive threshold during both normoxia and hypoxia compared with control animals. Because reports suggest that opioid and serotonergic mechanisms may be involved in mediating the sympathoinhibition that occurs with hemorrhage, we hypothesized that opioid and/or serotonergic systems are stimulated during hemorrhage under conditions of acute hypoxia and suppressed after chronic exposure to hypoxia and are thus responsible for the altered cardiovascular responses to hemorrhage under each condition. Control and chronically hypoxi rats were administered either the opioid receptor antagonist naltrexone (1 mg/kg), the selective 5-hydroxytryptamine receptor subtype 3 (5-HT3) serotonergic receptor antagonist MDL-72222 (0.5 mg/kg), or their respective vehicles intravenously before hemorrhage was initiated during normoxia or hypoxia (FIO2 = 0.12). In control animals, pretreatment with naltrexone increased the hemorrhage was initiated volume required to achieve hypotension in hypoxic but not normoxic conditions. Naltrexone had no effect on hypotensive threshold in chronically hypoxic animals under conditions of either normoxia or hypoxia. In addition, MDL-72222 had no effect on hypotensive threshold in either control or chronically hypoxic animals in either normoxic or hypoxic conditions. We conclude that endogenous opioids may contribute to the reflex hypotension that occurs during hypoxic hemorrhage in control rats, while no such involvement is evident in chronically hypoxic animals. Furthermore, peripheral 5-HT3 receptors are not likely involved in this response during either normoxic or hypoxic hemorrhage in control or chronically hypoxic rats.