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Nichols DE. 
“Potential Psychotomimetics Bromomethoxyamphetamines And Structural Congeners Of Lysergic Acid”. 
Diss.Abstr.Intern. B. 1973;34(6):2539-2540.
Consideration of various structural elements in LSD led to the proposal that a phenethylamine moiety may be the active pharmacophore. The hypothesis was advanced that LSD may act at two separate receptors in the brain. The LSD D-ring was considered as the other potentially active portion of the molecule. Dopaminergic receptors were proposed as one possible site of action; 5-HT or adrenergic sites as the other(s). Six bromomethoxyamphetamines were synthesized. Test - ing for an effect on the conditioned avoidance response in rats showed that psychotomimetic activity resided only in com - pounds with a pare bromine. Comparison of activity data with values for fluorescence intensity and with HOMO values for the corresponding chloromethoxyamphetamines indicated that no correlations exist and it is concluded that the pare sub - stituent has most importance in conferring metabolic stability on the molecule. A discussion of the importance of stereochemistry of the methoxylated amphetamines is included. An improved asym - metric synthesis was developed to give a high-yielding method for preparing methoxylated amphetamine isomers of high enantiomeric purity. A rigid analog of DOM (STP) was prepared as an LSD AC-ring congener. The compound, 5,8-dimethozy-o-methyl - 1,2,3,4-tetrahydro-2-naphthylamine, was prepared from 2,5 dimethoxy-3-methyl benzaldehyde and an improved method was developed for preparing this aldehyde in large amounts. Attempts were made to prepare N-methyl-5-carbethoxy-3 - piperidone as an intermediate for synthesis of substituted 3 phenyl -1,2, 5, 6 -tetrahydropyridine -5 -carboxylic acid derivatives as LSD AD-ring congeners. Dieckmann cyclization of the resulting from reduction of the product of conden - sation between ethyl sarcosinate and formyl succinate led to a mixture of the piperidone and pyrrolidone ring systems. Under conditions used in work-up, the desired piperidone formed its diethyl ketal. The ketal proved surprisingly stabile - to acid hydrolysis. Possible explanations are offered for the formation and resistance to hydrolysis of the ketal.
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