Binding-site hypotheses

Interestingly, a comparison between the specific pharmacophore and the binding-site hypotheses vividly establishes the fact that the latter is definitely more acceptable and plausible physiochemically due to the fact that the ensuing overlap of the functional moieties in the process of binding to a receptor is found to be more restrictive than anticipating that the particular site does remain more or less fixed when getting bound to difierent ligands. 

Hydroxamic acids have been extensively investigated at Abbott, where a hypothetical binding site hypothesis was based on examination of many simple Gj-aralkylhydroxamic acids [294]. Several series of conjugated hydroxamic acids were explored based on this hypothesis, yielding potent 5-LO inhibitors (0.02-2 //M) exemplified by (116)-(119). The most potent of these (119) also inhibited purified porcine leukocyte 5-LO (0.5 //M) [202]. As other workers have found, A-methylation was beneficial for potency. Activity was also seen in a rat peritoneal anaphylaxis model following i.p. (0.2 mg/kg), but not oral, dosing [47]. 

Figure 3.27. (a)Pharmacophore hypothesis with correspondence of functional groups in drugs, A = A, B = B, C = C. (b) Binding-site hypothesis use of drugs with hypothetical binding sites attached (X, Y, and Z overlap). 

Fig. 15.4-4 Three ligand binding sites model for monoamine-related CPCRs illustrated by a rhodopsin-based 3D model of the 5-HTia receptor (left extracellular view right side view). We recently proposed a three binding site hypothesis for the molecular recognition of ligands at monoamine CPCRs by combining ...

M. Spedding, A three binding site hypothesis for the interaction of ligands with monoamine G-protein coupled receptors implications for combinatorial ligand design, Quant. Struct.-Act. Relat. 1999, 18, 561-572. 

Very recently, a third hypothesis has been pubHshed. Morita and co-workers [47] have suggested that the rpoH mRNA secondary structure itself acts as a thermosensor. In the absence of heat stress, the rpoH mRNA is folded into a secondary structure that occludes the ribosome binding site and the initiation codon. Upon heat shock, this structure is unfolded allowing ribosome binding and enhanced synthesis. 

Ishimaru, M, Kurumaji, A and Toru, M (1994) Increases in strychnine-insensitive glycine binding sites in cerebral cortex of chronic schizophrenics evidence for glutamate hypothesis. Biol. Psychiat. 35 84-95. 

Dr. Gibb s hypothesis regarding dopamine involvement, we thought that perhaps MBDB would not be neurotoxic because of a lack of effect on dopamine. But, in fact, it is neurotoxic as well, measured by whole-brain serotonin 5-HIAA and tritiated paroxetine binding sites. It is perhaps two-thirds the toxicity, on a molecular weight basis, of MDMA, but it is toxic. 

In addition to its relatively high affinity at postsynaptic 5-HT receptors, MDMA exhibited high affinity for 5-HT uptake sites and has been shown to increase the release of [ H]5-HT and block [ H]5-HT uptake in vitro. These data suggest that some of the actions of MDMA may be mediated at presynaptic binding sites. With respect to [ H]5-HT release, MDMA has been reported to increase the release of [ H]5-HT from brain synaptosomes (Nichols et al. 1982) and hippocampal slices (Johnson et al. 1986). With respect to uptake blockade, MDMA has been reported to competitively inhibit H-5-HT uptake in vitro (Shulgin 1986). Furthermore, the neurotoxic effects of in vivo administration of MDMA on serotonin terminals can be blocked by concomitant administration of the 5-HT uptake blocker citalo-pram (Battaglia et al. 1988b Schmidt and Taylor 1987). Additional evidence in support of the hypothesis that MDMA produces some of its... 

It has not yet been clarified whether the ring substituents interact directly with the binding site or affect the molecular characteristics of the DHP molecules in common. A recently used atomistic pseudoreceptor model for a series of DHP indicated a putative charge-transfer interaction was stabilizing the DHP-binding site complex [19]. To prove this hypothesis qualitative and quantitative analysis of the molecular orbitals of nine DHP derivatives (Fig. 9.11) was performed [18]. Charge-transfer (or electron-donor-acceptor) interactions are indicative of electronic... 

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