Structure-activity requirements

Various phenallcylamines were shown to produce either DOM-like or AMPH-like stimulus effects the structure-activity requirements for these activities are different from the standpoints of aromatic substitution patterns, terminal amine substituents, and optical activity. Thus, it has been possible to formulate two distinct SARs. It should be realized, however, that phenalkylamines need not produce only one of these two types of effects certain phenallcylamines can produce pharmacological effects like neither DOM nor AMPH. Moreover, they can produce effects that are primarily peripheral, not central, in nature (Glennon 1987a). The fact that an agent produced DOM- or AMPH-like effects does not imply that it carmot produce an additional effect conversely, if an agent does not produce either DOM- or AMPH-like stimulus effects, it is not necessarily inactive. 

From the discussion of compounds above, it can be seen that Class III elec-trophysiological activity can be elicited with a wide variety of structural types. At first glance there do not seem to be specific requirements to produce active compounds. When the structures of the selective Class III compounds (that is, concentration-dependent prolongation of APD with minimal (< 5 %) inhibition of F ax are compared, a pattern emerges which can be used to define structure activity requirements. A general structure for a selective Class III agent is presented in Figure 2.3. 

Gee KW, Bolger MB, Biinton RE, et al Steroid modulation of the chloride ionophore in rat brain structure-activity requirements, regional dependence and mechanism of action. J Pharmacol Exp Ther 246 803-812, 1988... 

We stress these assays because, while leading to the discovery of IAA, they imposed structure-activity requirements precluding study of the IAA conjugates--and possibly the discovery of other auxins. For a substance to be active in the assays required that they 1) permeate membranes in a cut tissue surface, 2) be transported to the growing zone, and 3) promote growth in that zone. Hopefully these three requirements may someday be studied independently. 

In 1978 we compared the structure activity requirements for the DA, (vascular DA) receptor with other putative DA receptors (1,4 )7 The limited SAR data available at that time supported the existence of at least two different DA receptors. DA-induced responses were divided into two categories on the basis of differences in agonist activity and potency series. The following phenomena appeared to be due to activation of DA2 receptors inhibition of norepinephrine release from the postganglionic sympathetic nerve inhibition of ganglionic transmission inhibition of prolactin release and emesis. Review of the current literature has not revealed exceptions to these correlations. 

The term classical cannabinoids refers to tricyclic THC-type cannabinoids. The SAR in these series have been quite extensively investigated in the past and several reviews have appeared [21, 91, 92], The structure-activity requirements formulated have withstood the erosion of time. Most of the published work refers to in vivo tests for effects now assumed to be due to CBi activation. Compton et al. have recently correlated binding to CBi with in vivo activity and have concluded that the requirements for binding to the cannabinoid receptor correlate well with activity across different species, and that receptor binding mediates most of the pharmacological effects of cannabinoids [93],... 

D. F. V. Lewis, B. G. Lake, T. J. B. Gray, and S. D. Gangolli, Arch, Toxicol., Suppl. 11, 39 (1987). Structure-Activity Requirements for Induction of Peroxisomal Enzyme Activities in Primary Rat Hepatocyte Cultures. 

The essential structure-activity requirements were the same as for the HI receptor except that the heteroaromatic ring had to contain an amidine unit (HN-CH-N ). These results are summarized in Fig. 13.7. 

Crossley (250) has investigated the structure activity requirements for FP receptor activation. Alteration of the length of the j3-chain, which can be altered from 8-11 carbon atoms, has little effect on activity. In addition, replacement of the carbon atoms in positions 17-21 in the p-chain with o gen alters... 

Through use of the virtually pure octopaminergic firefly system, we have now acquired some idea of the structure-activity requirements for activation of this octopamine-sensitive adenylate cyclase. Furthermore, by quantitating the octopamine agonist potencies of a large series of chemically-related derivatives, we are now in an excellent position to characterize octopamine receptors in other, less homogenous tissues as well as in other insect species. 

There is evidence indicating that the structure-activity requirements for excitation and inhibition are different for capsaicin analogues. Thus, the incorporation of certain long chain fatty acids in capsaicin analogues resulted in desensitising and analgesic activity but also decreased pungency. [56]. 

During the late 1970s and early 1980s most of our cannabis work was devoted to investigations on the structure-activity requirements (SAR) for cannabinoid activity and initial work on the therapeutic opportunities opened by the cannabinoids (Mechoulam and Carlini, 1978). Together with friends in South America, we found that some cannabinoids — including the nonpsychotropic CBD — were potent antiepileptics. We prepared nearly 1 kg of CBD, which was used in a clinical trial in Brazil (Cunha et al., 1980). The results were positive, but unformnately this work has not been further pursued, and CBD is not in clinical use. 

Cannabinoid structure-activity requirements (SAR) literature has primarily focused on CBj-receptor affinities of fatty acid ethanolamides, such as AEA and its analogs. Recently, however, Sugiura has begun to develop an SAR for 2-AG and its analogs based on a functional assay of Ca + mobilization (Sugiura et al., 1999 Sugiura and Waku, 2000). Because of their difference in basis, each of these SARs will be presented separately here. 

Foster PM, Lake BG, Cook MW, et al. 1981. Structure-activity requirements for the induction of testicular atrophy by butyl phthalates in immature rats Effect on testicular zinc content. In Snyder R, Parke DV, Kocsis JJ, et al., eds. Biological reactive intermediates-II Chemical mechanisms and biological effects, Part A. New York, NY Plenum Press, 445-452. 

In other new work the structure-activity requirements for antidepressant activity of amino acids coupled to the 17/3-amino position has been further evaluated. "... 

The concentration gradient for taurine across the heart cell membrane is approximately 400 1. In the isolated, perfused rat heart, taurine is taken up by an active transport process, which is saturable at taurine concentrations of 200 mM or higher. The process exhibits a Km of 45 mM and a Vmax of 32 nMole/g dry weight/min. The transport site is specific for 3 amino acids, showing no affinity for a amino acids. In addition, as discussed in more detail below, the structure-activity requirements for transport are amazingly... 

The structure-activity requirements of the taurine transporting system in the heart are quite precise. Compounds we have found to... 

Structure-activity requirements in the phenylisopropylamine series were... 

The structure-activity requirements for inhibition of acetylcholinesterase and NTE are different this is demonstrated by the fact that many OPs with powerful anticholinesterase properties do not have the capability to produce OPIDP. Thus, the OP chemical warfare nerve agents that are very potent anticholinesterases, have little propensity to cause OPIDP, ° although, at supralethal doses, sarin can cause delayed neuropathy in antidote-protected chickens while tri-o-cresyl phosphate, which has little anticholinesterase activity, is powerfully neuropathic. ... 

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