PubMed · 9031564
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J T McCracken, W Martin. 1997. Clonidine side effect.. https://doi.org/10.1097/00004583-199702000-00002
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WB 4101 (1)-related benzodioxanes were synthesized by replacing the ethylene chain separating the amine and the phenoxy units of 1 with a cyclopentanol moiety, a feature of 6, 7-dihydro-5-[[(cis-2-hydroxy-trans-3-phenoxycyclopentyl)amino]meth yl] -2-methylbenzo[b]thiophen-4(5H)-one that was reported to display an intriguing selectivity profile at alpha(1)-adrenoreceptors. This synthesis strategy led to 4 out of 16 possible stereoisomers, which were isolated in the case of (-)-3, (+)-3, (-)-4, and (+)-4 and whose absolute configuration was assigned using a chiral building block for the synthesis of (-)-3 starting from (+)-(2R)-2, 3-dihydro-1,4-benzodioxine-2-carboxylic acid ((+)-9) and (1S,2S, 5S)-2-amino-5-phenoxycyclopentan-1-ol ((+)-10). The aim of this project was to further investigate whether it is possible to differentiate between these compounds with respect to their affinity for alpha(1)-adrenoreceptor subtypes and the affinity for 5-HT(1A) receptors, as 1 binds with high affinity at both receptor systems. The biological profiles of reported compounds at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO and HeLa cells membranes expressing the human cloned alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors, respectively. Furthermore, the functional activity of (-)-3, (+)-3, (-)-4, and (+)-4 toward 5-HT(1A) receptors was evaluated by determining the induced stimulation of [(35)S]GTPgammaS binding in cell membranes from HeLa cells transfected with human cloned 5-HT(1A) receptors. The configuration of the cyclopentane unit determined the affinity profile: a 1R configuration, as in (+)-3 and (-)-4, conferred higher affinity at alpha(1)-adrenoreceptors, whereas a 1S configuration, as in (-)-3 and (+)-4, produced higher affinity for 5-HT(1A) receptors. For the enantiomers (+)-4 and (-)-4 also a remarkable selectivity was achieved. Functionally, the stereoisomers displayed a similar alpha(1)-selectivity profile, that is alpha(1D) > alpha(1B) > alpha(1A), which is different from that exhibited by the reference compound 1. The epimers (-)-3 and (+)-4 proved to be agonists at the 5-HT(1A) receptors, with a potency comparable to that of 5-hydroxytryptamine.
BACKGROUND: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer's disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms. METHODS: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied. RESULTS: CSF DOPA following yohimbine was higher in older and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects. CONCLUSIONS: During alpha-2 adrenoreceptor blockade in both aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance. This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder.
1. The effects of noradrenaline on neurotransmission at rat hippocampal synapses were investigated by recording autaptic currents in single neurons isolated on glial microislands. Noradrenaline reduced excitatory, but not inhibitory, autaptic currents in a pertussis toxin-sensitive manner, but the amine did not affect glutamate-evoked currents. 2. The inhibition of excitatory autaptic currents by noradrenaline was half-maximal at 0. 11 +/- 0.06 microM. The alpha2-adrenoceptor agonists UK 14 304 and clonidine were equipotent to noradrenaline in reducing these currents, whereas the alpha1-adrenoceptor agonist methoxamine and the beta-adrenoceptor agonist isoprenaline (isoproterenol) were ineffective. The reduction of excitatory autaptic currents by noradrenaline was not altered by the alpha1-adrenergic antagonist urapidil or the beta-antagonist propranolol, but reduced by the alpha2-antagonist yohimbine. The subtype-preferring antagonists rauwolscine and phentolamine (both at 0.3 microM) caused 9-fold and 36-fold rightward shifts in the concentration-response curve for the noradrenaline-dependent reduction of excitatory autaptic currents, respectively. Prazosine (1 microM) did not affect this concentration-response curve. 3. Noradrenaline reduced voltage-activated Ca2+ currents in excitatory, but not in inhibitory, microisland neurons. For comparison, the GABAB agonist baclofen reduced both excitatory and inhibitory autaptic currents and diminished voltage-activated Ca2+ currents in both types of neurons. The inhibition of Ca2+ currents by noradrenaline was half-maximal at 0.17 +/- 0.05 microM, and UK 14 304 and clonidine were equipotent to noradrenaline in reducing these currents. The noradrenaline-induced reduction of Ca2+ currents was antagonized by yohimbine, but not by urapidil or propranolol; the subtype-preferring alpha2-adrenergic antagonists displayed the following rank order of activity: phentolamine > rauwolscine > prazosine. 4. Noradrenaline did not affect K+ currents and failed to alter the frequency of miniature excitatory postsynaptic currents measured in mass cultures of hippocampal neurons. 5. These results show that noradrenaline regulates transmission at glutamatergic, but not at GABAergic, hippocampal synapses via presynaptic alpha2-adrenoceptors of the alpha2A/D subtype. This inhibitory action involves an inhibition of voltage-activated Ca2+ currents, but no modulation of spontaneous vesicle exocytosis or of voltage-activated K+ currents.