ABSTRACT
In the asymmetric unit of N-(3,5-diamino-6-chloropyrazin-2-ylcarbonyl)-N-(diaminomethylene)ammonium chloride methanol hemisolvate, C(6)H(9)ClN(7)O(+).Cl(-).0.5CH(4)O, there are two crystallographically different amiloride molecules. Crystallographically identical amiloride molecules are stacked one above the other, alternately rotated by 180 degrees. These stacks are arranged parallel to each other, forming layer A. The least-squares plane of the non-H atoms of the other molecules lying in layer B is tilted against the corresponding plane of the molecules in layer A by an angle of 79.89 (3) degrees. The methanol molecules and Cl(-) anions are located between these layers, although the methanol molecules are closer to layer A.
Subject(s)
Amiloride/chemistry , Diuretics/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Models, MolecularSubject(s)
Aporphines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Animals , Aporphines/chemistry , Aporphines/pharmacology , Binding, Competitive , Brain/metabolism , CHO Cells , Cricetinae , Crystallography, X-Ray , Cyclic AMP/biosynthesis , In Vitro Techniques , Molecular Conformation , Rats , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Novel rigidified (R)-aporphine derivatives were synthesized from (R)-1,11-carbonylaporphine by ring expansion reactions. The structures of the novel analogues were assigned by NMR spectroscopy and X-ray crystallography. The compounds showed moderate affinities and selectivities at serotonin S-HT1A and 5-HT7 and dopamine D2A receptors.
Subject(s)
Aporphines/metabolism , Dopamine Agonists/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Animals , Aporphines/chemical synthesis , Combinatorial Chemistry Techniques , Dopamine Agonists/metabolism , Hippocampus/chemistry , Humans , Molecular Conformation , Protein Binding , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1 , Serotonin Receptor Agonists/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.
Subject(s)
Aporphines/chemical synthesis , GTP-Binding Proteins/metabolism , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Animals , Aporphines/chemistry , Aporphines/metabolism , Binding, Competitive , CHO Cells , Cricetinae , Crystallography, X-Ray , Hippocampus/metabolism , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Molecular Conformation , Radioligand Assay , Rats , Receptors, Serotonin, 5-HT1 , StereoisomerismABSTRACT
The four stereoisomers of the antimuscarinic 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine have been prepared by a method involving chromatographic separation of the racemic diastereoisomers as borane complexes. The relative and absolute configurations of the stereoisomers were determined by X-ray crystallographic methods. The crystal structure of (2'R,3R)-3-(2,3-dihydrobenzofuran-2-yl)quinuclidine.HCl.H2O contains two independent molecules with different conformations of both the quinuclidine moiety and the dihydrofuran ring.
Subject(s)
Muscarinic Antagonists/chemistry , Quinuclidines/chemistry , Receptors, Muscarinic/metabolism , Animals , Crystallography, X-Ray , Guinea Pigs , Muscarinic Antagonists/metabolism , Quinuclidines/metabolism , StereoisomerismABSTRACT
A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.