Structure-activity relationships substitution

For a structure-activity relationship study on 5//-pyrido[4,3-(j]indoles (y-carbolines), we needed both 1-unsubstituted 271 and 1-substituted methyl 2,3-dihydro-3-oxo-5//-pyrido[4,3-(j]indole-4-carboxylates 272 (Scheme 42). 

Nishioka and Fujita78) have also determined the Kd values fora- and (S-cyclodextrin complexes with p- and/or m-substituted phenyl acetates through kinetic investigations on the alkaline hydrolysis of the complexes. The Kd values obtained were analyzed in the same manner as those for cyclodextrin-phenol complexes to give the Kd(X) values (Table 5). The quantitative structure-activity relationships were formulated as Eqs. 30 to 32 ... 

Structure activity relationships, i.e., the total pattern of change in a biological activity as a function of chemical structure, typically derived from a comparison within a chemical series so that the biological effects of substitution at each structural position may be determined and correlated. 

Medvedev AE, Veselovsky AV, Shvedov VI, Tikhonova OV, Moskvitina TA, Fedotova OA, et al. Inhibition of monoamine oxidase by pirlindole analogues 3D-QSAR and CoMFA analysis. / Chem Inf Comput Sci 1998 38 1137-44. Miller JR, Edmondson DE. Structure-activity relationships in the oxidation of para-substituted benzylamine analogues by recombinant human liver monoamine oxidase A. Biochemistry 1999 38 13670-83. 

Most relevant for the affinity for A9-THC and analogs to CB-receptors are the phenolic hydroxyl group at C-1, the kind of substitution at C-9, and the properties of the side chain at C-3. Relating to the structure-activity relationships (SAR) between cannabinoids and the CB-receptors, many different modified strucfures of fhis subsfance group were developed and fesfed. The most important variations include variations of the side chain at the olivetolic moiety of the molecules and different substitutions at positions C-11 and C-9. One of the most popular analogous compounds of A9-THC is HU-210 or (-)-trans-ll-OH-A8-THC-DMH, a cannabinoid with a F,l-dimethylheptyl side... 

The structure/activity relationships for the methisazone, 3a, derivatives against adenoviruses and poxviruses have been shown to be similar [78]. Pearson and Zimmerman [79] demonstrated that all three types of polioviruses are inhibited by 2-acetylpyridine JV-dibutylthiosemicarbazone, which is similar to 3a, by blocking viral RNA synthesis. A 3-substituted triazinoindole derivative of isatin was effective against several strains of rhinovirus in tissue culture the mechanism of action is unknown [80]. 

Tessel, RE., and Woods. J.H. Meta-substituted Nethylamphetamine selfinjection responding in the rhesus monkey Structure-activity relationships. J Pharmacol Exp Ther 205(2) 274-281, 1978. 

Tessel. RE. Woods, J.H. Counsell, R.E. and Lu, M. Structure-activity relationships between meta-substituted N-ethylamphetamines and locomotor activity in mice. J Pharmacol Exp Ther 192(2) 310-318, 1975. 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Another characteristic of PCP which has been studied with great interest over the last 5 years, is the ability of PCP to produce a discriminative stimulus in monkeys, rats, and pigeons. As discussed elsewhere in this volume, by Browne, the discriminative stimulus properties of PCP are shared not only by other members of the arylcycloalkylamine class, but by psychotomimetic benzo-morphans and substituted dioxolanes. The structure-activity relationships (SAR) within and between these classes are virtually identical to those found when studying the displacement of 3H-PCP from its binding site in rat brain membranes. This correlation... 

Some structure-activity relationships of a further developed R4, R5 alkyl/cycloalkyl series (2a-o, Fig. 10, Table 1) were also investigated. This study [69] revealed structural features that favored allosteric enhancing activity, such as benzoyl lipophilic substitution and thiophene 4-alkyl substitution, while other features, such as thiophene 5-bulky substitution, favored antagonistic properties. Upon further analysis, a... 

Kirkiacharian S, Thuy DT, Sicsic S, Bakhchinian R, Kurkjian R, Tonnaire T (2002) Structure-activity relationships of some 3-substituted-4-hydroxycoumarins as HIV-1 protease inhibitors II. Farmaco 57 703-708... 

Numerous patents have appeared describing derivatives of 5 and 6 as potential PAMOR antagonists. With the exception of 5 and 6, there are no peer-reviewed publications on structure-activity relationships, in vivo activity, or other preclinical data for the new agents. As viewed from the patent literature, introduction of polar substitutents into the morphinan scaffold is the preferred peripheralization strategy. 

Anderson, G. M., Ill, Castagnoli, N., Jr., and Kollman, P. A. (1978) Quantitative structure-activity relationships in the 2,4,5-ring substituted phenylisopropylamines. In NIDA Research Monograph Series 22, edited by G. Barnett, M. Trsic, and R. Willette, pp. 199-217. U. S. Govt. Printing Office, Washington, D. C. 

Kline, T., Benington, F., Morin, R. D., and Beaton, J. M. (1982) Structure-activity relationships in potentially hallucinogenic N,N-dialkyltryptamines substituted in the benzene moiety. J. Med. Chem., 25 908-913. 

Methoxy-N,N-dimethyltryptamine (O-methylbufotenine 59) is hallucinogenic in man at a parenteral dose of approximately 6 mg (204). Numerous animal studies have shown that 5-OMeDMT is behaviorally quite active (16,65-67,71,178,184). This compound also produced limb-flick behavior in cats (119) and the serotonin syndrome in rats (209). Glennon et al. (85) demonstrated that 5-OMeDMT serves as a discriminative stimulus in rats and have employed rats trained to discriminate 5-OMeDMT from saline to investigate the structure-activity relationships of various substituted N,N-dialkyltryptamine derivatives. The results of these studies have recently been reviewed (84). 

Gessner, P. K., Godse, D. D., Krull, A. H., and McMullan, J. M. (1968) Structure-activity relationships among 5-methoxy-N,N-dimethyltryptamine, 4-hydroxy-N,N-dimethyltryptamine (psilocin) and other substituted tryptamines. Life Sci., 7 267-277. 

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