Receptor Binding Studies: General Considerations
William C. Eckelman, Lelio G. Colombetti in Receptor-Binding Radiotracers, 2019
Ehrlich’s observations on the rigid structural requirements for antibody-antigen (and later chemotherapeutic agent-parasite) interactions provided the basis for the earliest, and one of the most productive modes of inquiry into receptor biochemistry, the structure-activity relationship (SAR). In this approach, it is assumed that there is a high degree of complementarity between the stereochemical configuration of a compound and the site with which it interacts. Comparisons of biological potency and chemical composition provide information on minimal structural requirements for effective drug action, suggest the presence of specific chemical groups within the binding site, permit the subclassification of receptors which recognize the same biological ligand, provide direction in the design of new synthetic drugs and afford insight into the relationship between receptor agonists and antagonists, the effects of which are frequently elucidated subsequent to interaction with overlapping sites. The application of molecular orbital theory has promised to extend the usefulness of SAR studies. In certain variations of this approach, attention is shifted away from “atom-to-atom” resemblances between molecules acting at a common site to a consideration of the overall electrostatic potential energy contours which determine the approach and the sites of interaction involved in the earliest stages of ligand recognition by a receptor (e.g., References 3 and 4). These long-range intermolecular forces during the early stages of drug-receptor interaction may be the greatest source of “specificity” in the interaction.4
Imaging Neuroreceptors to Study Drug Action in Living Human Brain
Edythe D. London in Imaging Drug Action in the Brain, 2017
Dewey et al. (1990a) also examined the muscarinic cholinergic system in an indirect manner by virtue of its interaction with the D2 dopaminergic system. By employing unlabeled cogentin prior to baboon imaging studies, they demonstrated decreases in 18F-N-methylspiperone binding to the striatum. Although the mechanism of the coinjected decreases in binding is not yet clear and may involve complex modeling approaches, the demonstration of receptor interactions in this study was important pioneering work. Whether the endogenous changes were due to blood flow and tracer delivery of 18F-N-methylspiperone or changes in dopamine levels, which would affect meth-ylspiperone binding, or whether there is a down regulation of receptors is yet to be determined. Nevertheless, this work demonstrates an important extension of receptor binding assays that can interrelate drug interactions and drug action.
The Discovery Of Chemical Neurotransmission
Andrew P. Wickens in A History of the Brain, 2014
To explain these effects, Langley proposed that nicotine must act on some specialised part or ‘receptive substance’ of the muscle. In turn, the nicotine ‘receptor’ then used the chemical message in some way to initiate the biological effects inside the muscle cell. Langley also reasoned there must be two types of receptor: one capable of producing muscle contractions sensitive to nicotine; and the other sensitive to the inhibitory effects of curare that produced muscle paralysis. Although Langley did not literally use the word ‘receptor’, it was the first time this type of concept had been used to explain drug action. The receptor idea, however, was not entirely foreign as the term had been used successfully by Paul Ehrlich in 1900 in an immunological context. Consequently, there were many biologists who recog nised the feasibility of Langley’s idea. In fact, the receptor theory is one of the key break throughs in the modern history of pharmacology, allowing a better understanding of drug action, and supporting the theory of chemical neurotransmission.
Herb–drug interactions: a mechanistic approach
Published in Drug and Chemical Toxicology, 2022
Ajay Kumar Sharma, Vijay Kumar Kapoor, Gurjot Kaur
Essentially, the extent of drug action is dependent on active drug molecules at the site of action which may be further dependent on drug’s metabolism in the body (liver) by enzyme systems. Cytochrome P450 (CYP) isoforms such as CYP1A1/2, CYP2B6, CYP2C8/9/19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A, are well reported to be important in the biotransformation of xenobiotics and endobiotics (Table 3). Interestingly, CYP450 enzymes showed the highest interactions (16 herbs in total) with the currently used herbs in the Indian medicinal systems. These interactions may have significant effects on the drugs that are taken in conjunction with the above herbs and are known as either substrates, inhibitors or inducers of the above-mentioned CYPs (Table 6). Table 6 describes the top four CYP450 enzymes and their currently known drug substrates, drug inhibitors and drug inducers. The herbs listed in Table 3 may have synergistic and/or antagonistic effects on the drug partners of these CYPs (Table 6). Such interactions have already been observed for Curcuma longa and Andrographis paniculata where CYP-mediated hydroxylation of tolbutamide, a CYP2C9 substrate, was inhibited either by alcoholic extract of the herb or by the isolated phytochemical constituent (andrographolide from Andrographis paniculata) (Al-Jenoobi 2010, Pekthong et al.2008).
Oligochitosan-pluronic 127 conjugate for delivery of honokiol
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Zhimei Song, Jingjie Sun, Peizong Deng, Feilong Zhou, Hongmei Xu, Yi Wen, Fangfang Teng, Di Ge, Runliang Feng
The premise for drug action is that drug’s effective concentration must reach around its acting site. The effective concentration depends on distribution of honokiol-loaded micelles around the fungi and honokiol release rate from the drug-loaded micelles. The results this section indicated that honokiol’s release from the drug-loaded micelles was slow in comparison with pure honokiol. It was reasonable that the slow release would reduce drug concentration around the fungi to below effective dosage and decrease contact between drug and fungi in honokiol-loaded micelles group, resulting in low antifungal activity. However, both of them showed same in vitro activities (Figure 5(A)). The former study confirmed that the drug-loaded micelles showed positive zeta potential originated from oligochitosan fragments. The positive charge made the honokiol-loaded micelles bind more efficiently with negative fungi. In addition, F127 is an amphiphilic copolymer having good surface activity. It can interact with various membrane components of the fungi cells to promote the accumulation of the honokiol-loaded micelles around the fungi cells. It also should change microviscosity of the membrane, leading to drug permeation into fungi. Hence, the similar activity of honokiol-loaded micelles to pure honokiol might be related to its higher cellular uptake.
Early outcomes, associated factors and predictive values of clinical outcomes of tandospirone in generalized anxiety disorder: a post-hoc analysis of a randomized, controlled, multicenter clinical trial
Published in Current Medical Research and Opinion, 2023
Yi Fu, Jian Lin Ji, Shen Xun Shi, Hai Yin Zhang, Guo Zhen Lin, Ying Li Zhang, Xiuli Li, Wen Yuan Wu
Early onset is important in the treatment of anxiety disorders. In recent years, more and more attention has been paid to the delay in time to clinical response. The efficacy outcomes of medication include onset, response, remarkable response and recovery. Early onset is reflected by symptom relief by ≥20% within 2 weeks of treatment. Early response is indicated by symptom relief by ≥50% within 4 weeks of treatment. Delayed response30 is considered for effects detected after 4 weeks of treatment. Based on the characteristics of drug action, the latter can be divided into three categories, i.e. fast, medium and slow, according to onset time. Fast refers to an onset within hours, medium refers to an onset within 7 days, and slow refers to an onset occurring at more than 14 days (2 weeks)31. There are many factors that affect the onset time for clinical improvement of a drug, and it takes a certain amount of time for a drug to onset, which is affected by the onset mechanism of the drug. The longer a person takes to respond response to the drug, the more likely they will not respond at all. Thus, several studies have shown28,29 that early drug response occurring in the first two weeks of drug treatment may predict treatment outcomes.