Agonists and Antagonists

The model was proposed by Snyder and co-workers and is shown in Figs. 12.35— 12.37).2 In the model, the agonist binding site is further away from the nitrogen and positioned axially with respect to it. The antagonist site is closer and positioned equatorially. 

A compound which is a pure antagonist would be forced to have a suitable substituent in the equatorial position. It is believed that the presence of a 14-OH group sterically hinders the isomer with the axial substituent, and forces the substituent to remain equatorial (Fig. 12.37). 

A new strategy in drug discovery, the selective optimization of side activities (the SOSA approach), has been formulated by Camille Wermuth [17,18 cf. Chapter I—1], In this approach, minor side activities of active compounds serve as the starting point for structural variations, ultimately to obtain analogues that now have the former side effect as their main activity. In this manner, nanomolar acetylcholinesterase (AChE) inhibitors as well as nanomolar muscarinic M, receptor and 5-HT3 receptor ligands could be derived from the antidepressant minaprine [17,18], 

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The actions of histamine are mediated through at least three distinct receptors defined pharmacologically by the actions of the respective agonists and antagonists. Reviews have been pubHshed (16,17). 

Two fundamental questions have emerged from these studies, ie, to what extent are agonists and antagonists binding similarly or differendy to the respective receptors, and can inhibitory compounds be developed that are active in vivo in humans as well as in vitro. An oxytocia antagonist that can block premature uterine contractions presents a promising example of the clinical utihty of such stmctures (47). Both linear as well as bicycHc modifications of these hormones also have provided new antagonist stmctures. 

Assay Methods for Evaluating Progestin Agonists and Antagonists. 

Modeling and Crystallographic Studies of Estrogen Agonists and Antagonists... 

Table 3. Agonists and Antagonists of Adenosine Triphosphate and Receptors...

Phentolamine (87), WB 4101 (88), and the site directed alkylatiag agent, chloroethylclonidine (CEC) (89) have been traditionally used to define a -receptors. Table 6 Hsts the various catecholamines and adrenoreceptor agonists and antagonists. 

Fig. 14. The cellular ionic environment depicting representative intracellular ionic concentrations and the equiUbrium potentials, for individual ions. Excitatory and inhibitory events are represented by — and +, respectively. Thus, K" channel agonists and antagonists are inhibitory and excitatory, respectively Ca " channel antagonists and activators are inhibitory and excitatory, respectively.

The quest for compounds that combined the analgesic properties of morphine, were nonaddictive, and lacked the side effects of nalorphine, led to the development of the dmgs shown in Table 3. These compounds have both agonist and antagonist activities. Nalbuphine (14) (23) and buprenorphine... 

Table 3. Drugs Exhibiting Both Opioid Agonist and Antagonist Activities...

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