ABSTRACT
A series of lobelane analogues has been synthesized and their structure-activity relationships at the vesicular monoamine transporter-2 (VMAT2) have been evaluated. The most potent analogues in this series were the cis-2,6-piperidino analogues, 25b, 27b, 28b, and 30b, with K(i) values ranging from 430 to 580 nM.
Subject(s)
Ganglionic Stimulants/chemical synthesis , Lobeline/analogs & derivatives , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Animals , Brain Chemistry , Ligands , Lobeline/chemical synthesis , Methamphetamine , Nicotinic Antagonists/chemical synthesis , Nicotinic Antagonists/pharmacology , Rats , Receptors, Nicotinic/drug effects , Structure-Activity Relationship , Substance-Related Disorders/drug therapy , Synaptic Membranes/chemistry , Vesicular Biogenic Amine Transport Proteins , Vesicular Monoamine Transport ProteinsABSTRACT
Title compound, 8, has been synthesized from isoquinolinone, 1 (an improved preparation for which is presented) and separated into its antipodes with D- and L-di-p-toluoyltartaric acids. These antipodes and the racemic precursor have been evaluated (and found active) in two in vivo systems for their effects. The most potent of the three, (+)-8, has an ED50 of 7.13 mumol/kg for inhibition of spontaneous activity and 7.45 mumol/kg for antinociception compared to 4.44 and 4.81 mumol/kg, respectively, for (S)-(-)-nicotine. Compounds (-)-8 and 7 are about one-fourth as potent. Isomer (+)-8 has the 3aR,9bS configuration, the latter corresponding to (S)-(-)-nicotine as determined by X-ray crystallography. However, (+)-8 failed to compete for [3H]-nicotine binding, and its pharmacological effects were not blocked by mecamylamine. These bridged nicotine analogs either are binding to an as-yet-unidentified nicotinic receptor or they represent a novel class of non-nicotinic analgesics.
Subject(s)
Ganglionic Stimulants/chemical synthesis , Ganglionic Stimulants/pharmacology , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Nicotine/analogs & derivatives , Analgesics/chemical synthesis , Animals , Behavior, Animal/drug effects , Depression, Chemical , Ganglionic Stimulants/metabolism , Isoquinolines/metabolism , Kinetics , Mice , Molecular Conformation , Molecular Structure , Nicotine/chemical synthesis , Nicotine/metabolism , Nicotine/pharmacology , Nicotinic Antagonists , Nociceptors/drug effects , Receptors, Nicotinic/physiology , Stereoisomerism , X-Ray DiffractionSubject(s)
Ganglionic Stimulants/chemistry , Receptors, Nicotinic/chemistry , Animals , Calorimetry , Computer Graphics , Drug Design , Electrochemistry/methods , Ganglionic Stimulants/chemical synthesis , Ganglionic Stimulants/pharmacology , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Binding , Protein Conformation , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/physiologyABSTRACT
Eight nicotinic agonists were synthesized, and their potencies were estimated by contracture of the frog rectus abdominis muscle. The most potent, 1-methyl-4-acetyl-1,2,3,6-tetrahydropyridine methiodide (3b), 50 times as potent as carbamylcholine, served as a template for the rest. Although all of the agonists could easily conform to the putative nicotinic pharmacophore, their potencies spanned a nearly 10,000-fold range. This pharmacophore, therefore, may be necessary but deficient. Computer-assisted molecular modeling studies helped to delineate additional factors that may contribute to potency. The factors are (1) the ground-state conformation, (2) superimposability of the hydrogen bond acceptor and the cationic head onto the template, (3) electrostatic potential at the cationic head and at the hydrogen bond acceptor site, and (4) the presence of a methyl group bonded to the carbon atom that bears the hydrogen bond acceptor. A new program, ARCHEM, was used to calculate and to visualize electrostatic potentials at the van der Waals surfaces of the agonists.
Subject(s)
Arecoline/analogs & derivatives , Ganglionic Stimulants/chemical synthesis , Animals , Arecoline/chemical synthesis , Arecoline/pharmacology , Computer Simulation , In Vitro Techniques , Models, Molecular , Muscle Contraction/drug effects , Rana pipiens , SoftwareABSTRACT
The recently discovered nicotinic agonist pyrido[3,4-b]norhomotropane [corrected] (PHT) as well as its N-methyl and 2'-methyl derivatives (syntheses reported herein) were compared with nicotine, nornicotine, and anatoxin a in a series of in vitro and in vivo assays. The results reveal that PHT possesses activity comparable to that of the highly potent agonist, anatoxin a. The inactivity observed relative to PHT of N-methyl- and 2'-methyl-PHT has helped to further define the structure-activity requirements of conformationally restricted nicotinoids.
Subject(s)
Ganglionic Stimulants/chemical synthesis , Pyridines/chemical synthesis , Tropanes/chemical synthesis , Animals , Brain/drug effects , Carbachol/analogs & derivatives , Carbachol/metabolism , Electric Organ/drug effects , Ganglionic Stimulants/metabolism , In Vitro Techniques , Nicotine/analogs & derivatives , Nicotine/metabolism , Pyridines/metabolism , Pyridines/pharmacology , Rats , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , Torpedo , Tropanes/metabolism , Tropanes/pharmacologyABSTRACT
The synthesis of cis and trans isomers of N,N-N-trimethyl-2-phenoxycyclohexylammonium bromide, cis-N,N,-N-trimethyl-2(2',6'-xylyloxy)cyclohexylammonium bromide, and N,N-dimethyl-3-phenoxypiperidinium bromide is described. Their structures and conformations were determined by NMR and uv absorption spectroscopy, the minimum torsional angles about the aryl-oxygen gond geing 20, 20, 80, and 27 degrees, respectively. Since the piperidinium compound stimulates ganglia, it is concluded the either planarity of the aryl--O--C system is not essential for this type of activity or receptor interaction can involve appreciable bond distortion. The absence of ganglion-stimulant activity in the remaining compounds indicates the need for a transoid arrangement of the O--C--C--N+ system.
Subject(s)
Choline/analogs & derivatives , Ganglionic Stimulants/chemical synthesis , Action Potentials/drug effects , Animals , Autonomic Fibers, Preganglionic/physiology , Blood Pressure/drug effects , Choline/chemical synthesis , Choline/pharmacology , Electric Stimulation , Female , Ganglia, Spinal/drug effects , In Vitro Techniques , Male , Molecular Conformation , Phenyl Ethers/chemical synthesis , Phenyl Ethers/pharmacology , Rabbits , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Preparation of analogs of 4-[N-(3-chlorophenyl) carbamoyloxy]-2-butynyltrimethylammonium chloride [1 (McN-A-343)], cis- and trans-4-[N-(4-chlorophenyl)carbamoyloxy]-2-butenyltrimethylammonium iodides (5 and 6), and the corresponding epoxides and cyclopropanes is reported. Pharmacological testing for ganglion-stimulating activity demonstrated that the trans olefin 6 and trans epoxide 8 have properties similar to 1, while the trans cyclopropane analog 10 was inactive. All cis compounds were inactive. The muscarinic ganglion-stimulating properties of the active compounds are interpreted in terms of similar fit at the receptor level by the alkyltrimethylammonium ion and the ether oxygen 5.7 A distant, as well as an electron-rich center midway between groups in the form of a double bond or unshared electron pairs. Comparison of smooth muscle and ganglion-stimulating properties of the compounds showed that trans epoxide 8 was the most selective for muscarinic ganglionic sites.
Subject(s)
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/chemical synthesis , Ganglionic Stimulants/chemical synthesis , Parasympathomimetics/chemical synthesis , Quaternary Ammonium Compounds/chemical synthesis , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/analogs & derivatives , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/pharmacology , Alkenes/chemical synthesis , Alkenes/pharmacology , Animals , Blood Pressure/drug effects , Cats , Cyclopropanes/chemical synthesis , Cyclopropanes/pharmacology , Epoxy Compounds/chemical synthesis , Epoxy Compounds/pharmacology , Ileum/drug effects , In Vitro Techniques , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Rabbits , Receptors, Cholinergic/drug effectsABSTRACT
Preparation of analogs of 4-[N-(3-chlorophenyl)carbamoyloxy]-2-butynyltrimethylammonium chloride (1, McN-A-343), the isomeric 2-trimethylammoniomethyl-3-[N-(4-chlorophenyl)carbamoyloxymethyl]bicyclo [2.2.1]hept-5-ene iodides (10-13), and the corresponding -bicyclo[2.2.1]heptane iodides (14-17) are reported. None of the compounds demonstrated ganglion-stimulating activity similar to 1 or antagonized the effects of 1.
Subject(s)
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Ganglionic Stimulants/chemical synthesis , Parasympathomimetics/chemical synthesis , Quaternary Ammonium Compounds/chemical synthesis , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/analogs & derivatives , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/pharmacology , Animals , Blood Pressure/drug effects , Bridged Bicyclo Compounds/pharmacology , Cats , Cycloheptanes/chemical synthesis , Cycloheptanes/pharmacologyABSTRACT
1 The guinea-pig isolated ileum has been used to estimate the ability of substituted phenylalkylonium salts (related to nicotine) to stimulate or block receptors in ganglia. The effects of hexamethonium were used to indicate which were the most specific ganglion stimulants; these were tested on the blood-pressure of pithed rats and for neuromuscular blocking activity on the rat diaphragm preparation.2m-Hydroxyphenylpropyltrimethylammonium and 3,4-dihydroxyphenethyltrimethylammonium (coryneine, ;quaternary dopamine') were the most active and specific ganglion stimulants but their usefulness in vivo may be limited by their neuromuscular blocking activity. The analogous tertiary compounds are being investigated.3 The affinities of substances which were blocking agents at ganglionic receptors were measured on the isolated ileum with m-hydroxyphenylpropyltrimethylammonium as agonist. The affinities of selected compounds for postganglionic receptors were measured in experiments on the ileum in the presence of hexamethonium and with carbachol as agonist. Some of the compounds were tested for neuromuscular blocking activity on the rat diaphragm.4 Phenylbutyldiethylamine had ganglion-blocking activity greater than pempidine and little postganglionic blocking or neuromuscular blocking activity. Its triethylammonium analogue had higher ganglion-blocking activity but had appreciable neuromuscular blocking activity.5 The aromatic ring system is not essential either for activity or affinity and the effects of substituents are not related to their effects on electron distribution. Stimulant activity is enhanced only by hydroxyl or amino groups in suitable positions; it is not improved by the presence of rigid features (double or triple bonds or a cyclopropane ring) in the side chain. Affinity is slightly increased by chloro or bromo groups in suitable positions but the unsubstituted compounds are among those with the highest affinity. Substituents have similar effects on affinity for postganglionic receptors, though for these receptors the compounds mostly have only about one-tenth of their affinity for ganglionic receptors.