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Biomedical subjects

A T Shulgin

Publications and source records attributed to A T Shulgin.

At least 37 records · Page 2Linked to original sources
PubMed1985

Ring-substituted beta-methoxyphenethylamines: a new class of psychotomimetic agents active in man.

Four members of a new class of psychotomimetic agents have been synthesized and evaluated in man. These compounds, which incorporate a beta-methoxy group onto a beta-phenethylamine sidechain, are the first reported psychotomimetics which are structural analogues of the neurotransmitter noradrenaline. These substances are more potent than the corresponding phenethylamines (lacking a beta-methoxy group) but less potent than the correspondingly substituted amphetamine derivatives.

Adult↗
PubMed1985

Iodine-122-labeled amphetamine derivative with potential for PET brain blood-flow studies.

The positron emitter 122I (t1/2 3.6 min) was collected from a xenon-122/iodine-122 (122Xe/122I) generator and incorporated into an amphetamine analog, 2,4-dimethoxy-N,N-dimethyl-5-[122I]iodophenylisopropylamine (5-[122I]-2,4-DNNA). The remote synthesis was achieved in 3 min with a 50% radioincorporation yield and a product radiopurity of greater than 98%. 5-[122I]-2,4-DNNA was injected into a beagle dog and a brain section imaged with positron emission tomography (PET). The uptake and retention of 5-[122I]-2,4-DNNA was compared to that of 82Rb+ in the same animal. Dynamic PET activity data were obtained 0-20 min postinjection of 5-[122I]-2,4-DNNA and showed rapid uptake by brain and good cerebral/extracerebral tissue distinction. A whole-body scan of a dog was also obtained with 5-123I-2,4-DNNA showing uptake in brain, lung, and other body organs. The feasibility of incorporating 122I into an extracted brain perfusion agent for use with PET is demonstrated.

Amphetamines↗
PubMed1984

Sulfur analogues of psychotomimetic agents. 3. Ethyl homologues of mescaline and their monothio analogues.

All possible monothio analogues of the mono-, di-, and triethoxy homologues of mescaline have been synthesized and pharmacologically evaluated in man. Modifications at the ring position para to the ethylamine chain, either with a sulfur atom, a longer alkyl chain, or both, lead to compounds of high central nervous system activity. The 4-n-propoxy and 4-n-butoxy homologues and their corresponding 4-thio analogues were also synthesized and pharmacologically evaluated. The propyl homologues retain high potency, but a butyl group (either with or without a sulfur atom) leads to a decrease in activity. The m-ethyl or m-thio analogues retain some central action but the diethoxy and especially the triethoxy homologues are relatively inactive as psychotomimetic drugs.

Adult↗
PubMed1984

Radiohalogen-labeled imaging agents. 3. Compounds for measurement of brain blood flow by emission tomography.

The radioiodine-labeled amines currently available as brain-imaging agents, based on our previous work and that of others, are prepared either by exchange labeling or by direct iodination of a protected intermediate. The intrinsic slowness of these processes limits their potential for use with the positron-emitting 122I, as it has a half-life of only 3.6 min. This isotope has advantages of a low dose to the patient and availability from a generator containing the parent 20-h 122Xe. To develop a radiopharmaceutical in which 122I could be utilized, we prepared a number of secondary and tertiary amines (maintaining the 2,5-dimethoxy substitution pattern which allows direct iodination at the 4-position) with 131I. The organ distributions of these compounds were studied, and the best properties were found in the N,N-dimethyl homologue (2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine). This compound was successfully synthesized in a matter of seconds, with a chemical yield and radioactive purity both in excess of 90% and an incorporation efficiency of radioiodine of about 40%.

Amphetamines↗
PubMed1983

Sulfur analogues of psychotomimetic agents. 2. Analogues of (2,5-dimethoxy-4-methylphenyl)-and (2,5-dimethoxy-4-ethylphenyl)isopropylamine.

The two thio analogues of each of the well-known psychotomimetic drugs DOM [(2,5-dimethoxy-4-methylphenyl)isopropylamine] and DOET [(2,5-dimethoxy-4-ethylphenyl)isopropylamine] have been synthesized and pharmacologically evaluated in man. The 5-thio isomers are more potent as psychotomimetic agents than the 2-thio isomers but still represent a drop of an order of magnitude in potency from the sulfur-free counterparts. The dithio analogue of DOM was synthesized and found to be without central activity at a dosage of approximately 50 times the mean effective dose of DOM.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1981

Sulfur analogues of psychotomimetic agents. Monothio analogues of mescaline and isomescaline.

Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

Adult↗
PubMed1981

Photoelectron spectra of psychotropic drugs. 6. Relationships between the physical properties and pharmacological actions of amphetamine analogues.

The valence ionization potentials of seven additional members of a series of 2,4,5-trisubstituted amphetamines (1-phenyl-2-aminopropanes) were measured by UV photoelectron spectroscopy. These and previously published data provide experimental measures of the gross electron-donor ability of the aromatic rings of 23 amphetamines. Analogues bearing the 2,5-dimethoxy orientation were found to possess the lowest ionization potentials (IPs); for the analogously X-substituted compounds, the IPs increased in the order of 2,5-(OMe)2-4-X less than 2,4-(OMe)2-5-X less than 4,5-(OMe)2-2-X. Relationships between human psychotomimetic activity (MU), rabbit hyperthermia (SRU), serotonergic receptor affinity (pA2), and charge-transfer complex stabilities (KDNB) were evaluated statistically. A good correlation (r2 = 0.92) was established between the human and rabbit potencies, but poorer correlations were obtained between animal potencies and pA2's (r2 = 0.68-0.69) or KDNB's (r2 = 0.03!). Analysis of the regression relationships between these pharmacological measures and two physical properties, IP and lipid solubility (as modeled by log P), were explored. In general, greater potency is associated with decreasing IP and increasing log P. However, numerous exceptions to single parameter regressions are found. The unusually great potency of the 2,5-(OMe)2-4-X analogues, while qualitatively related to the physical properties, is quantitatively underestimated by these predictors. However, inclusion of a parameter (pi 4) which explicitly acknowledges the type of the 4-substituent leads to much improved correlations. These results support previous suggestions that 4-substituents interact directly with the receptor.

Amphetamines↗
PubMed1980

Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine).

The known central nervous system activity of 3,4-methylenedioxyphenylisopropylamine and its N-methyl homolog prompted the synthesis of a series of analogs with substituents on the nitrogen atom. Most of these analogs (R = alkyl, alkenyl, hydroxy, alkoxy, and alkoxyalkyl) were prepared by the reductive alkylation of 3,4-methylenedioxyphenylacetone with the appropriate amine and sodium cyanoborohydride. Hindered isomers were synthesized indirectly. Measurements of their pharmacological activity in several animal assays and in human subjects indicated that the central activity decreased with the increasing bulk of the N-substituent.

3,4-Methylenedioxyamphetamine↗
PubMed1980

Phenylalkylamines with potential psychotherapeutic utility. 2. Nuclear substituted 2-amino-1-phenylbutanes.

A series of 2-amino-1-(4-substituted-2,5-dimethoxyphenyl)butanes (Table V) was prepared as analogues of (R)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane (1a). 1-(2,5-Dimethoxyphenyl)-2-(N-phthalimido)butane (7) was utilized as a synthetic intermediate common to many of the target compounds. Animal data are presented indicating that most of these analogues have low hallucinogenic potential. Selected compounds were compared with 1a in an avoidance-response acquisition model which differentiates between 1a and the human hallucinogens DOM (2a) and DOET (2b). Structure-activity relationships of these analogues are discussed.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1980

[Research on the central activity and analgesia of N-substituted analogs of the amphetamine derivative 3,4-methylenedioxyphenylisopropylamine].

N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (MDA) were tested ror analgesic potency and influence on motor activity in mice following potency and influence on motor activity in mice following oral administration. These compounds also were tested for thei psychotomimetic potency in man. Unsubstituted MDA and its monoalkyl-homologs with a low number of C-atoms (N-methyl-, N-methyl-, N-ethyl-MDA) showed both enhancement of motor-activity in mice and psychotomimetic effects in man. MDA and N-methyl-MDA also showed an analgesic effec wthich was enhanced by the inclusion of a weakly labis group (N-mallyl, N-hydroxyethyl). These latter two compounds, however, did not influence motor-activity, which makes them more recommendable as possible analgesic compounds. Structural parallels between these compounds, morphine, endorphins and enkephalins, may explain their similar spectrum of pharmacological effects.

3,4-Methylenedioxyamphetamine↗
PubMed1979

Molecular connectivity analysis of hallucinogenic mescaline analogs.

The hallucinogenic (psychotomimetic) potency of 10 mescaline analogs was examined by molecular connectivity analysis. Potencies could be described by a two-term relating equation, which explained 94% of the variance in activity, on the basis of structural variation, 2,5-Dimethoxy substitution as well as the nature of the 4-position substituent played an important role in determining hallucinogenic potency. With the relating equation, reasonable potency predictions were made for six compounds not included in the initial investigation.

Hallucinogens↗
PubMed1978

An iodinated catecholamine congener for brain imaging and metabolic studies.

The iodinated O-methylated catecholamine congener, 4-iodo-2,5-dimethoxyphenylisopropylamine (4-I-DPIA), has potential as a new agent for imaging and metabolic studies of the brain and lung. The organ distribution and brain uptake of radioiodine-labeled 4-I-DPIA were studied in the dog and monkey by whole-body scanning, gamma-camera scintigraphy, and organ assay. The brain takes up 2% of the injected dose, with a half-time of 8 sec in the monkey, and the lung takes up 11.8%. An unusual finding was a concentration in the retina, five times that in any other CNS tissue. 4-I-DPIA may have potential in the imaging of normal brain tissues and thereby delineating nonfunctional areas damaged by infarction, trauma, or malignancy, and may also be useful in metabolic studies of catecholamine function. Adequate radioactivity can theoretically be administered with a quantity of 4-I-DPIA 1/10,000 of the pharmacologically active levels. The agent may also find application in lung imaging because of the high pulmonary uptake.

Amphetamines↗