Phentolamine Analogue 1

Bioisosteric phentolamine analogs as selective human alpha(2)- versus alpha(1)-adrenoceptor ligands

Phentolamine is known to act as a competitive, non-subtype-selective alpha-adrenoceptor antagonist. In an attempt to improve alpha(2)- versus alpha(1)-adrenoceptor selectivity and alpha(2)-adrenoceptor subtype-selectivity, two new chemical series of bioisosteric phentolamine analogs were prepared and evaluated. These compounds were evaluated for binding affinities on alpha(1)- (alpha(1A)-, alpha(1B)-, alpha(1D)-) and alpha(2)- (alpha(2A)-, alpha(2B)-, alpha(2C)-) adrenoceptor subtypes that had been stably expressed in human embryonic kidney and Chinese hamster ovary cell lines, respectively. Methylation of the phenolic hydroxy group and replacement of the 4-methyl group of phentolamine with varying lipophilic substituents yielded bioisosteric analogs selective for the alpha(2)- versus alpha(1)-adrenoceptors. Within the alpha(2)-adrenoceptors, these analogs bound with higher affinity at the alpha(2A)- and alpha(2C)-subtypes as compared to the alpha(2B)-subtype. In particular, the t-butyl analog was found to be the most selective, its binding at the alpha(2C)-adrenoceptor (Ki=3.6 nM) being 37- to 173-fold higher than that at the alpha(1)-adrenoceptors, and around 2- and 19-fold higher than at the alpha(2A)- and alpha(2B)-adrenoceptors, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities of selected compounds from the bioisosteric series on human alpha(1A)- and alpha(2C)-adrenoceptors. Thus, the results with these bioisosteric analogs of phentolamine provide a lead to the rational design of potent and selective alpha(2)-adrenoceptor ligands that may be useful in improving the therapeutic profile of this drug class for human disorders.

Efficacy of phentolamine mesylate in reducing the duration of various local anesthetics

Background: To evaluate changes in the effectiveness of phentolamine mesylate in combination with different local anesthetics (LAs) and vasoconstrictors. A prospective randomized double-blind study was conducted with 90 patients divided into three groups, with each group being administered one of three different LAs: lidocaine 2% 1/80,000, articaine 4% 1/200,000, and bupivacaine 0.5% 1/200,000.
Methods: We compared treatments administered to the mandible involving a LA blockade of the inferior alveolar nerve. Results were assessed by evaluating reduction in total duration of anesthesia, self-reported patient comfort using the visual analog pain scale, incidence rates of the most common adverse effects, overall patient satisfaction, and patient feedback.
Results: The differences among the three groups were highly significant (P < 0.001); time under anesthesia was especially reduced for both the lip and tongue with bupivacaine. The following adverse effects were reported: pain at the site of the anesthetic injection (11.1%), headaches (6.7%), tachycardia (1.1%), and heavy bleeding after treatment (3.3%). The patients' feedback and satisfaction ratings were 100% and 98.9%, respectively.
Conclusions: Efficient reversal of LAs is useful in dentistry as it allows patients to return to normal life more readily and avoid common self-injuries sometimes caused by anesthesia. Phentolamine mesylate reduced the duration of anesthesia in the three studied groups, with the highest reduction reported in the bupivacaine group (from 460 min to 230 min for the lip and 270 min for the tongue [P < 0.001]).

Vasoactive intracavernous pharmacotherapy

The use of vasoactive intracavernous pharmacotherapy for the treatment of impotence is rapidly expanding because of its effectiveness and the rarity of short-term complications. To minimize complications, careful selection of candidates, cautious dosage determination, and thorough instruction on injection technique are mandatory. Sustained erection should be treated with alpha-adrenergic agents after 4 to 6 hours. Frequent follow-up is mandatory after home injection begins to detect the development of penile abnormalities. Longer follow-up and additional studies are required to determine the types and incidences of long-term adverse effects of the technique.

Phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex

Possible antagonist effects of phentolamine at presynaptic serotonin autoreceptors were studied in slices of the occipito-parietal cortices of the rabbit and the rat. The slices were preincubated with 3H-serotonin and then superfused and stimulated electrically with single pulses or pulse trains. Nitroquipazine 1 mumol/l, a compound that inhibits the high affinity neuronal uptake of serotonin, was present in the superfusion medium in all one pulse-experiments as well as in experiments in which the effect of unlabelled serotonin was examined. In rabbit cortical slices, unlabelled serotonin reduced the single pulse-evoked overflow of tritium. Its concentration-response curve was not changed by the selective alpha 2-adrenoceptor antagonist idazoxan 1 mumol/l but was shifted to the right by phentolamine 1 and 10 mumol/l. Phentolamine 10 mumol/l also shifted to the right the concentration-inhibition curve of the selective 5-HT1-receptor agonist 5-carboxamidotryptamine. When the slices were stimulated by trains of 30 pulses at 3 Hz, phentolamine 1 and 10 mumol/l but not 0.1 mumol/l increased the evoked overflow of tritium, the maximal increase amounting to 178%; its effect was enhanced in the presence of nitroquipazine 1 mumol/l plus idazoxan 10 mumol/l (a drug combination that, when given alone, slightly increased the evoked overflow of tritium). The serotonin receptor antagonist metitepin at concentrations of 0.01-1 mumol/l also increased the overflow of tritium elicited by 30 pulses/3 Hz, the maximal increase amounting to 280%; its effect was potentiated in the presence of nitroquipazine 1 mumol/l plus idazoxan 10 mumol/l but was abolished or almost abolished in the presence of nitroquipazine 1 mumol/l plus phentolamine 10 mumol/l (a drug combination that, given alone, greatly increased the evoked overflow of tritium). When slices were stimulated by trains of 360 pulses at 3 Hz, there was no apparent antagonism of phentolamine 10 mumol/l against the inhibitory effect of unlabelled serotonin. In rat brain cortex slices, unlabelled serotonin reduced the overflow of tritium elicited by 4 pulses delivered at 100 Hz. Again, phentolamine 10 mumol/l shifted the concentration-response curve to the right. It is concluded that phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex with pA2 values of 6.44 and 5.95, respectively. Previous failures to detect the antagonistic effect against exogenous agonists were probably due to stimulation conditions that led to marked endogenous autoinhibition of serotonin release.(ABSTRACT TRUNCATED AT 400 WORDS)

Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.