Effects of tiodazosin, praxosin, trimazosin and phentolamine on blood pressure, heart rate and on pre- and postsynaptic alpha-adrenergic receptors in the rat.

Subcutaneous administration of tiodazosin (0.1-3 mg/kg), prazosin (0.01-1 mg/kg), trimazosin (10-30 mg/kg) and phentolamine (0.1-3 mg/kg) to conscious spontaneously hypertensive rats (SHR) produced graded decreases in blood pressure with the order of potency being prazosin > tiodazosin > phentolamine > trimazosin. Heart rate was elevated predominantly only by phentolamine and this was consistent with the activity of this agent for both pre- and postsynaptic alpha-adrenergic receptors. In contrast, tiodazosin, prazosin and trimazosin showed selectivity only for postsynaptic alpha-adrenergic receptors. Acute oral administration of tiodazosin and prazosin indicated tiodazosin to be about 1/2 as potent as prazosin. However, chronic administration of equivalent doses of the two compounds for 25 and 52 days via the drinking water indicated approxiately equivalent, sustained reductions in blood pressure. Furthermore, at the end of the 52-day chronic dosing period tiodazosin caused appreciably less alpha-adrenergic receptor antagonist activity than prazosin as assessed by the norepinephrine dose-pressor response profiles. These results indicate that following chronic dosing with tiodazosin in the rat other mechanisms besides alpha-adrenergic receptor antagonist activity are probably contributing to the antihypertensive effect in the rat.

Pharmacological effects of a combination of butorphanol and acetaminophen.

Isobolographic analysis was used to study in mice the combined oral analgetic action of butorphanol, a new centrally acting analgetic, and acetaminophen, an antipyretic analgetic. Combinations of butorphanol-acetaminophen exhibited analgetic effects which were greater than were expected from just an additive analgetic action of each drug. Consequently, a significant synergistic effect occurred after the simultaneous oral administration of butorphanol and acetaminophen. Furthermore, oral administration of butorphanol-acetaminophen mixture to conscious dogs at approximately 20 times the recommended human dose resulted in little or no effect on aortic blood pressure and arterial blood pH,pCO2 and pO2. Heart rate was slightly reduced and this resulted in a small increase in the PR interval and a prolongation of the QT interval of the lead II surface electrocardiogram.

Analgesics and narcotic antagonists in the benzomorphan and 8-oxamorphinan series. 5.

3-Methoxy-8-oxamorphinans 9 have been prepared from the corresponding 5-allyl-9alpha-hydroxy-2'-methoxy-2-methyl-6,7-benzomorphans 7. The former compounds were transformed to the 3-hydroxy-8-oxamorphinans 6, a class of potent analgesics and analgesic-antagonists. In ring C of the morphinan nucleus substitution of 8-CH2 with oxygen enhanced both analgesic and antagonist activities, while replacement of hydrogen with a methyl group at C-14 in these compounds enhanced antagonist activity and decreased analgesic activity. Tetrahydrofuranobenzomorphans 3 and 3-hydroxy-8-oxaisomorphinans 4 displayed lower levels of activity. Structural requirements for antagonist activity are discussed.

5-allyl-9-oxobenzomorphans. 3. Potent narcotic antagonists and analgesics-antagonists in the series of substituted 2',9beta-dihydroxy-6,7-benzomorphans.

5-Allyl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan methiodide (1) has been converted in a selective two-step process to the corresponding 9beta-hydroxy intermediates 4 and 6, which in turn were transformed via modified von Braun demethylation-acylation to the amides 11 and 21, respectively. These were reduced and demethylated to give a series of 5-allyl-2',9beta-dihydroxy-2-substituted 6,7-benzomorphans 13 and 23, some of which have been found to be highly potent narcotic antagonists and/or analgesics. The resolution of the most interesting compounds (23a and 23b) and pharmacological properties of the optical isomers are also described. Reduction of the double bond in 13 and 23 to give 14 and 24, with one exception, did not appreciably alter pharmacological profiles, while cyclization to the tetrahydrofuranobenzomorphans 25 substantially reduced the level of activities.

The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic.

Butorphanol, a new, totally synthetic morphinan, which is chemically related to naloxone, has been demonstrated to have both analgesic and narcotic antagonist properties. In rodent antiwrithing analgesic tests, butorphanol was 4 to 30 times more potent than morphine and dl-pentazocine, respectively. As an antagonist, butorphanol was about equivalent to nalorphine and 30 times more potent than dl-pentazocine. On the basis of the naloxone-induced mouse jumping test and the lack of substitution in withdrawn morphine-dependent mice, it is estimated that the potential for physical dependence of butorphanol will be less than that of dl-pentazocine but greater than that of nalorphine and dl-cyclazocine. Animal data also show that agonistic actions of butorphanol, such as respiratory depression and miosis, reach ceiling effects which are lower than those seen with morphine with an increase in dosage. Thus, butorphanol differed from morphine which exhibited agonist effects in a dose-related manner. Butorphanol showed weak to moderate central depressant properties at doses which were considerably higher (greater than 100 X) than those producing analgesia. Minimal cardiovascular and respiratory effects were seen with butorphanol in conscious dogs.

Oxilorphan (l-N-cyclopropylmethyl-3,14-dihydroxymorphinan): a new synthetic narcotic antagonist.

Oxilorphan is a fully synthetic morphinan derivative containing the 14-hydroxy group characteristics of naloxone and naltrexone. As a narcotic antagonist, oxilorphan was 4 times more potent than dl-cyclazocine, equipotent to naloxone and about one-fourth as potent as naltrexone parenterally. Duration studies in rodents were inconclusive, but in antagonism of morphine analgesia and miosis in the dog, oxilorphan was longer acting than naloxone and equivalent to dl-cyclazocine. Oxilorphan was inactive in the conventional animal thermal analgesic tests. However, oxilone did exhibit relatively weak analgesic activity in preventing phenylquinone-induced abdominal contraction at doses about 700 times higher than those required for antagonist activity. The analgesic potency of oxilorphan was only 120 and 1/300 the potency of morphine and dl-cyclazocine, respectively, but was significantly greater than naltrexone and naloxone. Mice chronically treated with increasing doses of oxilorphan failed to exhibit withdrawal jumping after naloxone challenge. General central nervous system activity studies showed oxilorphan to be relatively free from central side effects at doses at which dl-cyclazocine produced pronounced effects.

A new method for the evaluation of analgesic activity using adjuvant-induced arthritis in the rat.

A bioassay was developed for the assessment of analgesic activity by using pain resulting from a reproducible pathological condition. The vocalization displayed by rats with adjuvant-induced polyarthritis was defined as an expression of pain, and a decrease of this response was established as specifically demonstrating analgesic activity. This method was capable of detecting the analgesic activity of morphine-like and narcotic antagonist-type analgesics, as well as the activity of the antipyretic analgesics. The relative potencies of known analgesic agents determined with this technique closely approximated the potencies of these analgesics in man. The instrumentation for recording and measuring the vocal response of arthritic rats is described.