Affinity structure-activity relationships

Poso A, R Juvonen and J Gynther 1995. Comparative Molecular Field Analysis of Compounds wii CYP2A5 Binding Affinity. Quantitative Structure-Activity Relationships 14 507-511. 

Quantitative Structure—Activity Relationships. Many quantitative stmcture—activity relationship (QSAR) studies of progestins have appeared in the Hterature and an extensive review of this work is available (174). QSAR studies attempt to correlate electronic, steric, and/or hydrophobic properties to progestational activity or receptor binding affinity. A review focusing on the problems associated with QSAR of steroids has been pubUshed (175). 

Colquhoun D (1998) Binding, gating, affinity and efficacy the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. BrJ Pharmacol 125 924—947... 

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... 

Mokrosz JL et al. (1995) Structure-activity relationship studies of CNS agents, XIX Quantitative analysis of the alkyl chain effects on the 5-HTlA and 5-HT2 receptor affinities of 4-alkyl-1-arylpiperazines and their analogs. Arch Pharm (Weinheim) 328(2) 143-148... 

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... 

Measurement of dissociation equilibrium constants, which is of particular value in receptor classification and in the study of structure/activity relationships, where the effects of changes in chemical structure on affinity (and efficacy) are explored. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

Lopez-Rodriguez, M.L., Rosado, M.L., Benhamu, B., Morcillo, M.J., Fernandez, E. and Schaper, K.-J. (1997) Synthesis and structure-activity relationships of a new model of arylpiperazines. 2. Three-dimensional quantitative structure-activity relationships of new hydantoin-phenylpiperazine derivatives with affinity for 5-HTIA and oq receptors. A comparison of CoMFA models. Journal of Medicinal Chemistry, 40, 1648-1656. 

From interesting new ligands, a substructure or similarity search will reveal compounds that can be tested by the same NMR methods, so that some knowledge about the structure-activity relationship is built up. This can lead to optimization of the ligand and to increased binding affinity, although improvement by more than an order of magnitude... 

Brock BJ, Waterman MR. 2000. The use of random chimeragenesis to study structure/function properties of rat and human P450cl7. Arch Biochem Biophys 373(2) 401 Colquhoun D. 1998. Binding, gating, affinity and efficacy the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. Br J Pharmacol 125(5) 924. 

---