Evaluation of the alpha 2‐adrenoceptor blocking properties of buspirone and ipsapirone in healthy subjects. Relationship with the plasma concentration of the common metabolite 1‐(2‐pyrimidinyl)‐piperazine.

Abstract

1 Because the 5-HTlA agonist anxiolytic azapirones have a common a2-adrenoceptor antagonist metabolite, 1-(2-pyrimidinyl)-piperazine (IPP), we measured central and peripheral a2-adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day-1 for 4 days and 10 mg on day 5), ipsapirone (15 mg day-'for 4 days and 5 mg on day 5) or placebo. 2 Clonidine decreased blood pressure, heart rate, oral body temperature, salivary excretion, plasma noradrenaline, 3,4-dihydroxyphenylglycol (DHPG) concentrations, increased plasma growth hormone but did not modify plasma insulin and C-peptide concentrations. Treatments tended to modify only the effect of clonidine on growth hormone (P = 0.07). 3 The azapirones reduced clonidine induced prolongation of choice reaction time (P = 0.015) and tended to antagonise clonidine induced fall in critical flicker fusion frequency (P = 0.066). 4 Only buspirone reduced total reaction time and increased critical flicker fusion threshold measured 12 h after the evening dose and these effects were correlated with the residual plasma lPP concentration which was higher on buspirone than on ipsapirone (2.76 ,ug 1-1, 95% CI:1.3-4.22 vs 0.65 ,ug I1-, 95% CI: 0.32-0.98, P = 0.006). 5 Mean AUC of the IPP plasma concentrations after the last dose of treatments were 3.7 times greater with buspirone than with ipsapirone (P = 0.0011). The AUC ipsapirone/AUC IPP ratio was 6.45 and the AUC buspirone/AUC lPP ratio was 0.076. 6 The formation of the common metabolite IPP is greater with buspirone than with ipsapirone. Buspirone but not ipsapirone (both given in therapeutically equivalent doses) exerted a psychostimulatory effect and this could be attributed to the higher plasma lPP concentrations found with buspirone. 7 A clearcut antagonism of clonidine actions by IPP could not be demonstrated probably because the ratio of the exogeneous a2-adrenoceptor agonist (clonidine) to the endogenously formed a2-adrenoceptor antagonist (1 PP) could not be controlled.

The Partial 5-Hydroxytryptamine1A Receptor Agonist Buspirone does not Antagonize Morphine-induced Respiratory Depression in Humans

“…The buspirone metabolite 1‐PP is a weak agonist at 5‐HT 1A receptors, with a 20 times lower potency than buspirone 21 . 1‐PP, in contrast to buspirone, also has α 2 ‐receptor antagonist activity 47 . The reversal of morphine‐induced respiratory depression by α 2 ‐antagonists in the conscious rat 48 suggests that 1‐PP is potentially contributing to the overall effects of buspirone on respiration.…”

N-Dealkylation of Arylpiperazine Derivatives: Disposition and Metabolism of the 1-Aryl-Piperazines Formed

“…Some derivatives are agonists at certain 5-HT receptors but antagonists at others, as exemplified again by mClPP which has agonistic activity at the human 5-HT 2C subtype but antagonist action at 5-HT 2B and 5-HT 7 receptors [6][7]. Some have more affinity and selectivity for other neurotransmitter receptors and systems; 1-(2-pyrimidinyl)-piperazine (PmP or 1-PP) and 1-(2-pyridinyl)piperazine (PdP) and its derivatives, for example, bind with high affinity to alpha 2 sites, acting in vivo as alpha 2 -adrenoceptor antagonists in man and animals [8][9][10][11].…”

Actions of α2 adrenoceptor ligands at α2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for α2A adrenoceptors

“…azaspirone anxiolytic agents, such as buspirone and tandospirone). This is due to their metabolism in vivo to 1-(2-pyrimidinyl)piperazine (1-PP), which is an α 2 adrenoceptor antagonist (Mennini et al 1987;Blier et al 1991;Berlin et al 1995). Although the affinity of 1-PP has been investigated in vitro for native rat (r) 5-HT 1A receptors (Mennini et al 1987) and in vivo for inhibition of electrically evoked hippocampal post-synaptic potentials (EPSP, Manahan-Vaughan et al 1995), they have not been characterised at human (h) 5-HT 1A receptors.…”