PubMed · 11397828
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P Cohan, S G Korenman. 2001. Erectile dysfunction.. https://doi.org/10.1210/jcem.86.6.7576
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BACKGROUND: Alteration in noradrenergic regulation as well as alteration in the hypothalamic-pituitary-adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms. METHODS: This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol. RESULTS: Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels. CONCLUSIONS: Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. The effect on cortisol supports the above conclusion and is consistent with HPA axis perturbation in opioid dependence as reported in other studies and extends these observations to stable methadone-maintained patients. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients.
WB4101 (1)-related compounds 5-10 were synthesized, and their biological profile at alpha(1)-adrenoreceptor (AR) subtypes and 5-HT(1A) serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors. Moreover, their receptor selectivity was further determined in functional experiments in isolated rat prostate (alpha(1A)), vas deferens (alpha(1A)), aorta (alpha(1D)), and spleen (alpha(1B)). In functional assays, compound 5 was the most potent at alpha(1D)-ARs with a reversed selectivity profile (alpha(1D) > alpha(1A) > alpha(1B)) relative to both prototype 1 and phendioxan (2) (alpha(1A) > alpha(1D) > alpha(1B)), whereas compound 8, bearing a carbonyl moiety at position 1, was the most potent at alpha(1A)-ARs with a selectivity profile similar to that of prototypes. The least potent of the series was the trans isomer 6, suggesting that optimum alpha(1)-AR blocking activity in this series is associated with a cis relationship between the 2-side chain and the 4-phenyl ring rather than a trans relationship as previously observed for the 2-side chain and the 3-phenyl ring in 2 and related compounds. Binding affinity results were not in complete agreement with the selectivity profiles deriving from functional experiments. Although a firm explanation was not available, neutral and negative antagonism and receptor dimerization were considered as two possibilities to account for the difference between binding and functional affinities. Finally, compound 5 was selected for a modeling study in comparison with 1, mephendioxan (3), and open phendioxan (4) to achieve information on the physicochemical interactions that account for its high affinity toward alpha(1d/D)-ARs.
A peripheral 5-HT(2A) receptor-mediated hemodynamic change prompted formation of indole-2,3-dione, an endogenous inhibitor of atrial natriuretic peptide (ANP) receptor binding and G protein-mediated intracellular signaling (IC(50): 0.4 microM). This effect was significantly suppressed by dexamethasone, indomethacin and the 5-HT(2) receptor antagonists, ketanserin or ritanserin. 5-HT(2A) receptor-mediated acute hemodynamic change was not modified significantly by indomethacin, prazosin or propranolol pretreatment. A tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, but not a dopamine beta hydroxylase inhibitor, diethyldithiocarbamate, abolished the 5-HT(2A) receptor-mediated increase in indole-2,3-dione. Exogenous indole-2,3-dione induced a significant increase in plasma catecholamine levels and decrease in urine volume. A 5-HT(2A) receptor-mediated decrease in capillary flow may have caused an inflammatory process and peripheral sympathetic activation via ANP signaling inhibition. 3,4-dihydroxyphenylalanine (DOPA)/dopamine may contribute to the progression of inflammation or the generation of a precursor of indole-2,3-dione. The observation that indole-2,3-dione abolished angiotensin AT(1) receptor-mediated NADPH activation in both human umbilical vein endothelial cells and smooth muscle cells at 20 microM may suggest that sulfhydryl-reactive indole-2,3-dione could influence mitochondrial function and cellular redox states via flavoenzyme inhibition and/or regulation of dehydrogenase-oxidase conversion.