The discovery and development of buspirone: A new approach to the treatment of anxiety

New, James S.

doi:10.1002/med.2610100302

Cited by 74 publications

(19 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The log[agonist ratio] of buspirone is higher than that of the full agonist R-8-OH-DPAT despite the fact that in vivo the intrinsic efficacy of buspirone is similar to that of the partial agonist S-8-OH-DPAT. This discrepancy might be caused by buspirone's activity at other receptors present in the in vivo test assay (New, 1990). Figure 4B shows the relationship between the intrinsic activity in vivo for the effect on body temperature in rats found for the 5-HT 1A receptor and in vitro measure for efficacy log[agonist ratio].…”

Section: Discussionmentioning

confidence: 99%

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Zuideveld

Graaf²,

Newgreen³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The pharmacokinetic-pharmacodynamic (PK-PD) correlations of seven prototypical 5-HT 1A agonists were analyzed on the basis of a recently proposed semi-mechanistic PK-PD model for the effect on body temperature. The resulting concentration-effect relationships were subsequently analyzed on the basis of the operational model of agonism to estimate the operational affinity (pK A ) and efficacy (log ) at the 5-HT 1A receptor in vivo. The values obtained in this manner were compared with estimates of the affinity (pK i ) and intrinsic efficacy (log[agonist ratio]) in a receptor-binding assay. Between 5-HT 1A agonists wide differences in in vivo affinity and efficacy were observed, with values of the pK A ranging from 5.67 for flesinoxan to 8.63 for WAY-100,635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide] and of the log ranging from Ϫ1.27 for WAY-Poor correlations were observed between the in vivo receptor affinity (pK A ) and the affinity estimates in the in vitro receptor binding assay (pK i ; r 2 ϭ 0.55, P Ͼ 0.05), which could in part be explained by differences in blood-brain distribution. In contrast, a highly significant correlation was observed between the efficacy parameters in vivo (log ) and in vitro (log [agonist ratio]; r 2 ϭ 0.76, P Ͻ 0.05). Thus by combining the previously proposed semi-mechanistic PK-PD model for the effect on body temperature with the operational model of agonism, a full mechanistic PK-PD model for 5-HT 1A receptor agonists has been obtained, which is highly predictive of the in vivo intrinsic efficacy.Recently a semi-mechanistic pharmacokinetic-pharmacodynamic model for the effects of 5-HT 1A agonists on body temperature has been proposed, which is based on dynamical systems analysis. It has been demonstrated that this model can be used to estimate both the in vivo potency and the intrinsic activity of 5-HT 1A agonists. In the mean time, this model has been successfully applied to characterize the in vivo concentration-effect relationships of several 5-HT 1A agonists including R-and S-8-OH-DPAT, flesinoxan, and buspirone (Zuideveld et al., , 2002a(Zuideveld et al., , 2002b. Furthermore, the in vivo affinity of the 5-HT 1A receptor antagonist WAY-100,635 could be estimated on basis of the analysis of the competitive interaction with R-8-OH-DPAT (Zuideveld et al., 2002b).The previously proposed model is semi-mechanistic in the sense that it uses a mechanistic model for the characterization of the transduction process. Specifically, 5-HT 1A agonists cause lowering of body temperature by modulation of the set-point for maintenance of the body temperature in a direct concentration-dependent manner . Therefore a mechanism-based set-point model, which is based on dynamical systems analysis, was proposed and successfully implemented in the integrated PK-PD model to describe the complex time profile of the effects of 5-HT 1A Article, publication date, and citation information can be found at

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Zuideveld

Graaf²,

Newgreen³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Furthermore its effect can be antagonized by selective 5-HT 1A receptor antagonists (Koenig et al, 1988;Cryan et al, 1999) and its selectivity over other receptors that may also mediate a hypothermic response, e.g., the ␣ 2 -AR (Dilsaver et al, 1989;MacDonald et al, 1989), -opioid (OP3) (Spencer et al, 1988), dopamine D 3 (Barik and de Beaurepaire, 1998) and adenosine A 1 receptors (Malhotra and Gupta, 1997) is high (New, 1990;Gobert et al, 1995). 1-PP on the other hand has affinity for both the 5-HT 1A (K D ϭ 1035 nM ϭ 94 ng/ml) and the ␣ 2 -AR (K D ϭ 40 nM ϭ 3.6 ng/ml) (Gobert et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Buspirone is a selective 5-HT 1A agonist that is used clinically as an anxiolytic drug (for reviews on its pharmacological properties, see New, 1990 andFulton and Brogdon, 1997). In vivo buspirone is metabolized into 1-(2-pyrimidinyl)-piperazine (1-PP), which also possesses affinity to the 5-HT 1A receptor.…”

Section: Introductionmentioning

confidence: 99%

“…Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine 1A agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.Buspirone is a selective 5-HT 1A agonist that is used clinically as an anxiolytic drug (for reviews on its pharmacological properties, see New, 1990 andFulton and Brogdon, 1997). In vivo buspirone is metabolized into 1-(2-pyrimidinyl)-piperazine (1-PP), which also possesses affinity to the 5-HT 1A receptor.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

Zuideveld

Rusiç-Pavletiç

Maas

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokineticpharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with setpoint control. Both buspirone and 1-PP behaved as partial agonists relative to R-(ϩ)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine 1A agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.Buspirone is a selective 5-HT 1A agonist that is used clinically as an anxiolytic drug (for reviews on its pharmacological properties, see New, 1990 andFulton and Brogdon, 1997). In vivo buspirone is metabolized into 1-(2-pyrimidinyl)-piperazine (1-PP), which also possesses affinity to the 5-HT 1A receptor. This metabolite could therefore contribute to the effect of buspirone (Bianchi et al., 1988;Manahan-Vaughan et al., 1995;Cao and Rodgers, 1997). At present there is limited quantitative information on the magnitude of this effect. In theory the contribution of the metabolite to the effect is determined by the relative concentrations of buspirone and 1-PP, their relative in vivo potency and intrinsic activity, and the nature of the pharmacodynamic interaction between the two.Recently we have developed a physiological pharmacokinetic-pharmacodynamic (PK-PD) model to quantitatively characterize the pharmacodynamics of 5-HT 1A receptor agonists in vivo using the hypothermic effect as a pharmacodynamic endpoint (Zuideveld et al., 2001(Zuideveld et al., , 2002a. The hypothermic response is considered a robust marker of 5-HT 1A activity (Millan et al., 1993;Cryan et al., 1999). It has been shown that the PK-PD model allows for the estimation of the in vivo potency and intrinsic activity of a wide array of different 5-HT 1A agonists such as R-8- -100,635), and Flesinoxan (Zuideveld et al., 2001, 2002a, 2002b. In the present investigation we apply this model to determine the relative in vivo po...

show abstract

“…Although the neurochemical mechanisms responsible for buspirone's anxiolytic activity were believed initially to involve dopamine, this possibility was by no means as certain as the fact that the pharmacological activity of buspirone did not directly involve the more traditional benzodiazepine-GABA-chloride ionophore complex (New 1990). Thus, the almost exclusive grip on anxiety that was held by the benzodiazepines for nearly 30 years was loosened and, during the subsequent years since buspirone's introduction, numerous attempts have been made to characterize the bases of its pharmacological activity.…”

mentioning

confidence: 98%

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

Barrett¹,

Vanover²

1993

Psychopharmacology

151

View full text Add to dashboard Cite

The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT1 receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT1A drugs in conflict procedures. Although chronic administration of 5-HT1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT2 and, perhaps, 5-HT3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT1C/2 and 5-HT3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

show abstract

The discovery and development of buspirone: A new approach to the treatment of anxiety

Cited by 74 publications

References 118 publications

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

Contact Info

Product

Resources

About

The discovery and development of buspirone: A new approach to the treatment of anxiety

Cited by 74 publications

References 118 publications

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

Contact Info

Product

Resources

About

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats