Biomedical subjects

S M Efange

Publications and source records attributed to S M Efange.

6 recordsLinked to original sources

PubMed1992

Lipophilic amino alcohols with calcium channel blocking activity.

A series of novel lipophilic amino alcohols, analogs of the anticholinergic drug vesamicol, were evaluated for Ca2+ channel blocking activity. The effects of these drugs on depolarization-induced intracellular free Ca2+ concentration ([Ca2+]i) transients were examined in single NG108-15 cells and dorsal root ganglion (DRG) neurons in culture. [Ca2+] was recorded with the Ca2+ indicator Indo-1 and a dual emission microfluorimeter. Structure-activity studies indicated that features required for Ca2+ channel blocking activity were distinct from those required for anticholinergic activity. In particular, the Ca2+ channel blocking activity was insensitive to the configuration at the chiral center, whereas the anticholinergic activity was clearly enantioselective. One of the most active compounds, 3-(3-bromophenyl)-2-hydroxy-1-[1-(4-phenylpiperidinyl)]propane (2b), was characterized in more detail. This compound inhibited the dihydropyridine-sensitive Ca2+ channel response in NG108-15 cells, evoked by depolarization with 50 mM K+, with an IC50 of 5 microM. Field potential stimulation of DRG neurons elicited [Ca2+]i transients mediated by at least three Ca2+ channel subtypes; compound 2b inhibited the entire Ca2+ channel response with an IC50 of 1 microM. A key element required for Ca2+ channel blocking activity was the presence of an electron withdrawing substituent on the pendant phenyl ring. Modification of the amino alcohol structure may lead to more potent compounds with broad spectrum Ca2+ channel blocking activity. These structures provide a new chemical starting point for the development of Ca2+ antagonists.

Amino Alcohols↗

PubMed1992

Interaction of flexible analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of N-methyl-4-phenylpyridinium with highly purified monoamine oxidase A and B.

Sixteen analogs of N-methyl-1,2,3,6-tetrahydropyridine (MPTP) of varying degrees of flexibility have been studied as substrates of highly purified monoamine oxidases (MAO) A and B. The relative effectiveness of the various tetrahydropyridines as substrates of MAO A and B were evaluated in terms of the function turnover number/Km, as determined by initial rate measurements. The insertion of a methylene bridge between the phenyl and tetrahydropyridine moieties of MPTP to yield N-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, rendering the molecule more flexible, greatly enhances reactivity with MAO B, but not with MAO A, as compared with MPTP itself, in accord with data in the literature (Youngster et al., 1989a). The ethylene-bridged MPTP analog, on the other hand, is a far better substrate of both forms of MAO than is MPTP itself. The effect of molecular flexibility on the rate of oxidation of these compounds is obscured by substituents on the aromatic ring. Branching and rigidity were detrimental to the activity as substrates of both forms of MAO. Those analogs of 1 which contain small electron-withdrawing substituents in the phenyl ring were found to be more selective for MAO B, while those substituted with bulky groups were selectively oxidized by MAO A. The substrate binding site of MAO A probably contains a lipophilic pocket larger than that found in a similar site in MAO B.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1992

Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane: potential radiotracer for mapping central cholinergic innervation in vitro.

Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane, 5 (4-HIPP), was synthesized and evaluated as a simple vesamicol-like radiotracer for mapping cholinergic pathways in the brain. Both enantiomers of 5 exhibit significant accumulation (approx. 2% of injected dose) and prolonged retention (t1/2 greater than 3 h) within the rat brain. The accumulation of radioiodinated 5 in the rat brain was reduced by up to 70% in the presence of vesamicol and its analogs. The levorotary isomer (-)-4-[123I]HIPP exhibits significant accumulation in the monkey brain, with a half-life of about 9 h. Radioiodinated 5 may therefore be a useful tool for studying cholinergic pathways in the brain.

Animals↗

PubMed1992

Computer-aided radiopharmaceutical design.

The ultimate goal of a QSAR analysis is prediction, which depends on the elaboration of the most appropriate set of molecular descriptors. As such, molecular description is the nucleus of QSAR and in the absence of exhaustive molecular description, rational drug design may be greatly impeded. As previously discussed, computational methods such as quantum mechanics and molecular mechanics provide molecular description at a fundamental level which then enhances the descriptive capability and predictive power of a QSAR analysis. In recognition of these capabilities, semi-empirical molecular orbital methods and molecular mechanics now have been incorporated into or interphased with QSAR programs. Such integrated packages are being successfully used in computer-aided molecular modeling. Computer-aided molecular modeling can provide the three-dimensional structure of a molecule, its chemical and physical characteristics, comparisons of structures of different molecules, and visualization of complexes formed between them. From the foregoing, predictions may be made about how related new molecules may function. Thus, the combination of quantum and/or molecular mechanics and QSAR provides a formidable weapon in the chemist's armamentarium. The molecular modeling approaches are certainly more practical to use than physicochemical methods. They also provide electronic and thermodynamic data that are not available from x-ray crystallographic data. Of course, these techniques are not confined to radiopharmaceutical development and they also could aid in the development of contrast agents for radiography or magnetic resonance imaging. We believe that as computational resources and capabilities increase over the next decade, computer-aided drug design will become a standard procedure in all drug development laboratories.

Binding Sites↗

PubMed1991

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Nineteen analogs of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been used as probes to study the structural parameters that influence MAO-catalyzed oxidation. In this study, the efficiency of enzyme-catalyzed substrate oxidation was found to be unrelated to parameters such as the ionization potential, dipole moment, net atomic charge at C5 and the dihedral angle between the phenyl ring and the tetrahydropyridine moiety. Conformational analysis revealed that substitution at the C2' position of MPTP yields atropisomers. It is suggested that one of these atropisomers would be either inactive or substantially less active than the other. Therefore, the relative oxidative efficiency and toxicity of these compounds reported earlier may have been significantly underestimated. Based on the conformational analysis and other data, a rudimentary model of the MAO substrate site has been developed which partially explains the substrate specificities of MAO A and MAO B. Each substrate binding site can be divided into two regions, (a) an amine-binding pocket (for the tetrahydropyridine moiety), and (b) a 'bulky substituent' region (for the phenyl group and its substituents). The length of the substrate binding site (measured along the long axis of MPTP) is approximately 8.5 A, and the width of the 'amine-binding' pocket is approximately 2.5 A (from C3 to C5). The 'bulky substituent' region contains a central area for binding the phenyl group of MPTP. This central area is flanked by two hydrophobic pockets, P2' and P3'. In MAO A, the pocket P2'-A is oriented 45-135 degrees relative to the plane of the tetrahydropyridine moiety, with a radius of 3.1 A from C2' of the phenyl ring. The radius of a similar but smaller pocket, P2'-B, in MAO B, is approximately 2.7 A. In MAO B, the pocket P3'-B (radius 2.36 A from C3') is larger than a similar pocket P3'-A (radius 1.70 A from C3') in MAO A. The foregoing characterization suggests that differences in the size and topography of both of the substituent pockets play an important role in determining the substrate specificities of these two isozymes.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1991

Acyclic analogues of 2-(4-phenylpiperidino)cyclohexanol (vesamicol): conformationally mobile inhibitors of vesicular acetylcholine transport.

Several 1,3-disubstituted propan-2-ols and one alpha,beta-disubstituted ethanol (11i) were synthesized and evaluated as potential acyclic mimics of the vesicular acetylcholine transport inhibitor 2-(4-phenylpiperidinyl)cyclohexanol (1, vesamicol, AH5183). Analogues containing the 4-phenylpiperidyl fragment (11a, 11b) were more potent than those containing the 4-phenylpiperazyl moiety (11e, 11f). Substitution at the second terminal carbon of the propyl (or ethyl) fragment with simple lipophilic aryl substituents yielded potent inhibitors of vesicular acetylcholine storage, including (-)-11a and d-11i, which are equipotent with vesamicol. However, the activity of analogues containing bicyclic aryl groups was susceptible to aryl substitution patterns (11g vs 11h), indicating a definite receptor site topography. In addition, the inhibitory activity of these acyclic analogues was enantioselective, exhibiting a preference, similar to the parent vesamicol, for the levorotatory isomer [(-)-11a vs (+)-11a]. Therefore, the simple lipophilic acyclic vicinal amino alcohols may successfully mimic the biological activity of vesamicol.

Acetylcholine↗