Potency receptor structure

After choosing the lead , one may use knowledge of the receptor site to achieve potency or selectivity advantages. One may even be able to generate the lead based on knowledge of receptor structure alone (see Sections 3.2 and 3.3). Whether or not such knowledge of the receptor site is available, the methods outlined in this section can be applied in order to optimize drug properties to the point of selection for preclinical or phase 1 study. 

THE BRAIN S OWN MARIJUANA-LIKE NEUROTRANSMITTER The very high potency and structure of the cannabinoids contained within the marijuana plant enable them to cross the blood—brain barrier and bind to a receptor for the brain s very own endogenous cannabinoid neurotransmitter system. If this were not true, then the marijuana plant would be popular only for its use in making rope, paper, and cloth. The two currently identified neurotransmitters compounds (and there are probably more) in this system are anandamide, from the Sanskrit word amnia () meaning bliss, and 2-AG (2-arachidonoyl-glycerol). Unlike the other neurotransmitters that I ve discussed, these two endocannabinoids are not stored in synaptic vesicles. 

D-QSAR studies demonstrated that there could be more than one way to fit structure-activity data within a QSAR methodology. A receptor-independent 4D-QSAR study identified the hydrophobic nature of a HIV protease receptor site and helped in structural modification to improve the potency of the AHPBA inhibitors [241], A 4D-fingerprint-based QSAR model developed for AHPBA inhibitors of HIV was generated independent of any receptor structure or alignment information [126]. These models exhibited comparable statistical data with CoMFA, CoMSIA and H-QSAR approaches. This study proved that genuine representation of 3D and conformational properties of compounds is possible using this approach. 

In the uterus, the production of 3, S -cyclic AMP is induced by the activation of the /7-adrenergic receptors and followed by inhibition of the electrical and mechanical activities. The action of oxytocin may be partly due to its ability to prevent the formation of cyclic AMP. The role of the reactive disulfide groups in the peptide receptors has already been discussed. The complexity of the receptor structure is pointed out by the observation that metals potentiate specifically the action of S-S polypeptides on the rat uterus, in such a way that it becomes very sensitive to vasopressin when the perfusion fluid contains a metal The order of metal potency is... 

Detailed molecular features as well as events leading to the integration of toxins into lipid bilayers is not clear at this point, and is a subject of intense current research. While the available knowledge of the structure of a handful toxins such as cholera, Psudomonas exotoxin A and porin, some common factors are visible, no toxic motif(s) has been identified yet. Availability of three dimensional structure of an adequate number of toxins is likely to reveal interesting structural features. Another area of needed research is the characterization of receptors for toxins. In most cases, cell surface receptors hold the key of toxin entry and potency. Receptor knowledge will not only help develop antidotes against toxins, but also could also help our understanding of toxins themselves. 

The second application of the CFTI protocol is the evaluation of the free energy differences between four states of the linear form of the opioid peptide DPDPE in solution. Our primary result is the determination of the free energy differences between the representative stable structures j3c and Pe and the cyclic-like conformer Cyc of linear DPDPE in aqueous solution. These free energy differences, 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. The predicted low population of the cyclic-like structure, which is presumably the biologically active conformer, agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide. 

Adenosine Receptors. Figure 1 Structures of widely used AR agonists, both nonselective and selective. Affinities/potencies at the ARs are found in Table 2. (a) Nucleoside derivatives that are either nonselective or selective for A receptors (1-12). (b) Nucleoside derivatives that are selective for A2a. A2a/A2b (mixed), or A3 receptors (13-19). 

The neuropeptide Y (NPY) belongs to a family of peptides that includes peptide YY and pancreatic polypeptide, and it is associated with several diseases such as asthma, immune system disorders, inflammatory diseases, anxiety, depression and diabetes mellitus. NPY is found in the central and peripheral nervous system, and its biological functions are mediated by interactions with five receptor sub-types, i.e. Yl, Y2, Y4, Y5 and Y6. Several studies indicate that the feeding behavior is influenced by interactions between NPY and Yl and Y5. Deswal and Roy used Cerius descriptors and genetic function approximation QSAR to investigate the structural determinants for the inhibition potency of 24 compounds with the general structure 4 for the NPY Y5 receptor [31]. The best QSAR (H = 0.720,... 

Following on from this, and to further exemplify this pharmacophore model, Huffman [182] described a novel hybrid structure that combined the hydroxydibenzopyran ring of THC and the indole moiety of the AAIs into one molecule. It was found that the hybrid molecule (270) had a similar affinity (19 nM) for the CBi receptor in vitro as (67) (41 nM). The compound was also active in vivo in the mouse tetrad model of cannabimimetic activity and had comparable potency to (67) [182]. 

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... 

Hampson, AJ, Hill WA, Zan Phillips M, Makriyannis A, Leung E, Eglen, RM, Bornheim LM. Anandamide hydroxylation by brain lipoxygenase metabolite structures and potencies at the cannabinoid receptor. Biophys. Biochim. Acta 1995 1259 173-179. 

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