A wide array of selective and less selective 5HT1A receptor ligands has been developed. It has been shown that these compounds are of value in the treatment of anxiety disorders and depression. In addition they may be of value in therapeutic indications such as aggression, addiction, seizures, nausea, and neuroprotection. The mechanism of action of 5HT1A receptor ligands is not entirely resolved. It is believed however that differences in intrinsic efficacy at 5HT1A receptors in different areas in the brain are an important determinant of the therapeutic effect. Specifically so-called near-silent agonists are considered of great interest for a number of indications.
The regional distribution of 5HT1A receptors within the brain has been studied in many animal species including the rat, mouse, guinea pig, calf, cat, pig, monkey, and human. It has been shown to be similar in these species.1o5 In short, 5HT1A receptors are distributed throughout the CNS, but high concentrations are found in the hippocampus, septum, and amygdala, areas that are typically thought to be associated with the control of mood.106 Interestingly, differences in receptor reserve in various parts of the brain have been demonstrated. For example it has been shown that higher levels of receptor reserve are present in the raphe nuclei (mainly, presynaptic somatodendritic autoreceptors), compared to the hippocampus and hypothalamus (mainly postsynaptic receptors).107 Hence a ligand may act as a full agonist for a presynaptically mediated response, whereas at the same time it may behave as a partial agonist for a postsynaptically mediated response.
Upon administration of 5HT1A receptor agonists a series of responses is observed which are all potentially suitable for PK/PD characterization. These in vivo effects can be classified into four groups: physiological (e.g., induction of hypothermia), endocrinological (e.g., stimulation of corticosterone release), behavioral (e.g., induction of flat body posture or forepaw treading), and therapeutic-like effects (e.g., reduction of fear-induced ultrasonic vocalizations or immobility in the forced-swimming test).108 The hypothermic response is a continuous, reproducible, objective, sensitive, and selective 5HT1A receptor mediated response, making it an attractive pharmacodynamic endpoint in PK/PD investigations. It is well established that the hypothermic effect of 5HT1A receptor agonists is caused by a direct effect on the body's set-point temperature.109 The hypothermic effect of 5HT1A receptor agonists has been studied extensively and is considered one of the most robust 5HT1A receptor-mediated responses.110 It is considered the response of choice for the differentiation between full, partial, and silent agonists at the 5HT1A receptor.111 Furthermore, this effect can be observed both in rodents and in humans111 thus enabling the investigation of animal to human extrapolation.
In PK/PD experiments in chronically instrumented rats the time course of the hypothermic response was determined in conjunction with plasma concentrations for R-8-OH-DPAT, S-8-OH-DPAT, flesinoxan, buspirone, buspirone's active (and but nonselective) metabolite 1-PP, WAY-100,135, and WAY-100,635.43'112-114 Briefly, 8 days prior to the experiment, the rats were operated upon. Indwelling cannulae for drug administration and blood sampling as well as a telemetric transmitter in the abdominal cavity for the measurement of core body temperature were implanted. In the PK/PD experiments, conscious freely moving rats received an intravenous infusion of vehicle (saline) or active drug. The 5HT1A receptor ligands were administered in a wide range of doses (high, middle, and low), infusion rates (short, intermediate, and computer controlled) and combinations (R-8-OH-DPATwith WAY-100,635). In each experiment from each individual rat approximately serial blood samples were taken and subsequently analyzed to determine the time course of the drug concentration.43,112-114 Body temperature was measured continuously throughout the experiment using the telemetric system. The affinity and the in vitro efficacy (agonist ratio) of the various 5HT1A receptor agonists have been determined in a series of receptor binding assays.25
In investigations where the hypothermic response is studied in detail, complex effect versus time patterns have been observed suggesting the involvement of homeostatic control mechanisms.115,116 In order to characterize 5HT1A-agonist induced hypothermia in a mechanistic manner a mathematical model which describes the hypothermic effect based on the concept of a set-point116-118 and a general physiological response model29 has been proposed.43 Briefly, as an agonist binds to the 5HT1A receptor a stimulus, S is generated, which in turn drives physiological processes that lower the temperature. This stimulus, which is determined by the drug receptor interaction and hence the drug's affinity and efficacy, can be described by a sigmoid function where f(C) for example equals eqn  or . As S is assumed to be inhibitory, it is defined as S = 1 —f(C). As the drug concentration C changes with time, S changes as well, governing the first timescale of the model. The second timescale on which the model operates is governed by physiological principles. The model that describes the hypothermic response utilizes the concepts of the indirect physiological response model as described by Dayneka etal.(eqn ).29 In this model the change in temperature (7) is described as an indirect response to either the inhibition of the production of body heat or the stimulation of its loss, where kin represents the zero-order fractional turnover rate constant associated with the warming of the body and kout a first-order rate constant associated with the cooling of the body. The indirect physiological response model is combined with the thermostat-like regulation of body temperature. This regulation is implemented as a continuous process in which the body temperature is compared with a reference or set-point temperature (TSP). It is accepted that 5HT1A agonists elicit hypothermia by decreasing the value of the set-point temperature TSP, and hence TSP depends on the drug concentration C: TSP = TSP(C). It is assumed that TSP is controlled by the drug concentration C through eqn :
where T0 is the set-point value in the absence of any drug: T0 = TSP(0). Combining the indirect physiological response model with the thermostat-like regulation then yields:
in which X denotes the thermostat signal. The change in X is driven by the difference between the body temperature T and the set-point temperature TSPon a timescale that is governed by a. Hence when the set-point value is lowered, the body temperature is perceived as too high and X is lowered. To relate this decreasing signal to the drop in body temperature, an effector function X- g was designed, in which g determines the amplification. Raising this function to the loss term kout ■ T therefore facilitates the loss of heat. In eqn , body temperature and set-point temperature are interdependent and a feedback loop is created that can give rise to oscillatory behavior, as has been shown.43 The model is able to reproduce the observed complex effect versus time profiles, which are typically observed upon the administration of 5HT1A receptor partial agonists.
A population approach119 was utilized to quantify both the pharmacokinetics and pharmacodynamics of the 5HT1A receptor agonists. This enabled the successful characterization of the time course of the hypothermic effect in terms of physiological parameters and drug specific parameters such as potency and intrinsic efficacy. In the initial version of the model, the sigmoid-Emax model (eqn ) was used to describe the direct concentration effect relationships of the 5HT1A receptor agonists at the receptor in terms of potency and intrinsic activity. In a subsequent step, which aimed at the development of a fully mechanistic model, the sigmoid-Emax model was replaced by the operational model of agonism18 (eqn ). In this analysis the value of the system maximum Emax was constrained to the observed maximum effect for a full agonist R-8-OH-DPAT. The values of KA and t for the various partial agonists were estimated by directly fitting the operational model of agonism to the combined concentration-effect data. The values of KA and t are shown in Table 1 together with the corresponding estimates of affinity (Ki) and intrinsic efficacy (log[Agonist ratio]) in a receptor binding assay. The correlation between pKA and pKi based on [3H]-WAY-100,635 was rather poor (P>0.05) compared to similar in vivo/in vitro correlations observed for adenosine A1 agonists, synthetic opiates, and GABAa receptor agonists (see previous sections). Close inspection of this correlation showed that flesinoxan deviated from the line of identity. In fact, the correlation between the pKA and pKi became statistically significant when flesinoxan was excluded from the analysis (P<0.05). Recently Van der Sandt etal.120 have shown that active transport mechanisms (i.e., P-glycoprotein) at the blood-brain barrier are an important determinant of the brain distribution for flesinoxan. Thus it appears that complexities at the level of blood-brain distribution of flesinoxan explain the observed lack of correlation between in vitro and in vivo receptor affinity estimates.25 Between the in vivo and in vitro efficacy (log t and log[agonist ratio]) a significant correlation was found (P<0.05). The correlation between log t and log[agonist ratio] showed further that the in vivo 'test assay' was more sensitive for detecting 5HT1A activity then the agonist ratio. For example, the significant in vivo agonist activity demonstrated for WAY-100,135 was not detected in vitro.
Thus by combining the semimechanistic PK/PD model for the hypothermic effect of 5HT1A agonists with the operational model of agonism, a full mechanistic PK/PD model was obtained, which proved to be highly predictive of the in vivo intrinsic activity of ligands at this receptor. This is important, since the pharmacological and therapeutic properties of 5HT1A agonists are closely related to the degree of intrinsic activity at 5HT1A receptors. The ability of the in vivo assay to detect weak partial agonism underscores the importance of the use of in vivo models in the development of 5HT1A agonists as clinical agents.
An important advantage of mechanism-based PK/PD models is their optimal properties for quantitative extrapolation of pharmacological responses across species. To this end allometric scaling of the rat PD parameters of the set-point model to predict the response in humans for buspirone and flesinoxan has been applied. Parameters were extrapolated based on body weight (M) following simple power laws, according to
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