Recognition of Anesthetic Barbiturates by a Protein Binding Site: A High Resolution Structural Analysis

Barbiturates potentiate GABA actions at the GABAA receptor and act as central nervous system depressants that can induce effects ranging from sedation to general anesthesia. No structural information has been available about how barbiturates are recognized by their protein targets. For this reason, we tested whether these drugs were able to bind specifically to horse spleen apoferritin, a model protein that has previously been shown to bind many anesthetic agents with affinities that are closely correlated with anesthetic potency. Thiopental, pentobarbital, and phenobarbital were all found to bind to apoferritin with affinities ranging from 10–500 µM, approximately matching the concentrations required to produce anesthetic and GABAergic responses. X-ray crystal structures were determined for the complexes of apoferritin with thiopental and pentobarbital at resolutions of 1.9 and 2.0 Å, respectively. These structures reveal that the barbiturates bind to a cavity in the apoferritin shell that also binds haloalkanes, halogenated ethers, and propofol. Unlike these other general anesthetics, however, which rely entirely upon van der Waals interactions and the hydrophobic effect for recognition, the barbiturates are recognized in the apoferritin site using a mixture of both polar and nonpolar interactions. These results suggest that any protein binding site that is able to recognize and respond to the chemically and structurally diverse set of compounds used as general anesthetics is likely to include a versatile mixture of both polar and hydrophobic elements

INFRARED SPECTRA OF SIMPLE AMINES AND THEIR IONS

Author Institution: Institut d\'e Chimic, Universit\'e de Montr\'ealA preliminary account is given of a comparative study of infrared spectra of simple amines and their chlorohydrates. Primary, secondary, and tertiary amines and their respective ions are studied,-- aliphatic, aromatic and aza-compounds -- and a general view on these spectra is sought. The effect of lonization on the amino-groups is discussed on the basis of the NH stretching and bending bands. Other bands in the spectra give information on modifications in the structure of the hydrocarbon part of these molecules following ionization. All the amines and ions were examined in various media: liquid or solid, aqueous solutions if possible, and solution of the hydrochlorides in their own amines or other amines when the latter are liquids. Relations between spectra taken in these media change in a significant manner for different types of compounds. The results are compared with known ultraviolet data

THE INFRARED SPECTRA OF METHYL-AMMONIUM HALIDES AT LOW TEMPERATURES

$^{1}$R. D. Waldron, J. Chem. Phys. 21, 784 (1953).Author Institution: D\'epartment de Chimie, Universit\'e de Montr\'ealThe spectrum of methylammonium chloride was examined by $Waldron^{1}$. We have measured the spectra of the four methylammonium halides at $21^\circ C$, $-190^\circ C$ and at intermediate temperatures in the solid phase. The room temperature spectra are consistent with $C_{3v}$ symmetry. With the probable exception of the fluoride, the salts undergo phase changes at low temperatures and the symmetry is lowered. These compounds exhibit hydrogen bonding of the $\stackrel{+}{N}-H-X^{-}$ type (X = F, Cl, Br, I) with some regular changes from one halogen to the other. The spectra are discussed in detail

HYDROGEN BONDING IN THE AMINE HYDROHALIDES

Author Institution: Department de Chimie, University de Montreal“The infrared spectra of seventeen amine hydrohalides have been measured in the solid state, in aqueous solutions and in their conjugate amine and their $N^{+} H$ stretching and scissoring bands are discussed. The stretching bands of hydrogen bonded aliphatic and aromatic amine hydrohalides fall into the same part of the spectrum. In the solid state, the hydrogen bonds are of type $N^{+}-H-X$. The aliphatic amine salts usually exhibit many sharp bands while the aromatic amine salts have broad but composite bands. Tertiary amine salts show a hypsochromic shift in the order hydrochloride, hydrobromide, hydriodide; primary and secondary aliphatic amine salts show a slight bathochromic shift in the same order. Primary and secondary aromatic amine salts behave less regularly although in most cases the shift is hypsochromic. These facts can be explained qualitatively by considering the charge distribution in the ionized omino groups and the contribution of electrostatic and delocalization effects to the energy of the hydrogen bonds. The anharmonicity of the potential surface which causes the appearance of strong combination bands may lead to the broadening of bands or to many sharp bands. There is no parallelism in this case between shift and broadening of the bands. The assignment of a strong band which appears in many cases near $2000 cm^{-1}$ is discussed. The above mentioned characteristic band shifting is absent in the spectra of aqueous solutions and it is concluded that in this case hydrogen bonding is not of the $N^{+}-H-X$ but of the $N^{+}-H-O$ type.