The antihypertensive properties of a synthetic prostanoid: RS-93427.

The antihypertensive activity of RS-93427, a synthetic prostanoid, was evaluated in conscious restrained spontaneously hypertensive rats. RS-93427 possesses potent antihypertensive activity when administered orally, intraduodenally, intravenously, or subcutaneously but not topically. The blood pressure reducing activity of RS-93427 in normotensive rats was comparable to that in hypertensive animals. No signs of tolerance to the antihypertensive effects were observed following fourteen days of oral administration of RS-93427. The synthetic prostanoid minimally enhanced the orthostatic hypotensive responsiveness to vertical, head up, repositioning of the restrained rats. The relative usefulness of the platelet antiaggregatory and antihypertensive properties of RS-93427 will have to be determined by clinical studies.

Platelet aggregation inhibitory activity and vasodepressor activity of a series of bicyclo[3.2.0]hept-6-ylidene iminoxy alkanoic acids with modified lower side chains.

Prostacyclin analogues derived from modification of the lower side chain of the bicyclo[3.2.0]hept-6-ylidene iminoxyacetic acid (1) were studied in inhibition of in vitro and ex vivo platelet aggregation and in the spontaneously hypertensive rat. Iminoxyacetic acids (13a), (13b), (13c) and iminoxypropionic acid (14b) were 2.9, 3.0, 1.9 and 2.0 times respectively more potent than PGE1 in inhibiting ADP-induced aggregation of human platelets in vitro. Following intravenous administration at a dose of 90-110 micrograms/kg in the guinea pig, iminoxyacetic acids (13a), (13c) and iminoxypropionic acid (14b) showed a maximum inhibition of 82-92% with a half life in the range of 14-22 min. Following oral administration at a dose of 1 mg/kg in the guinea pig, iminoxyacetic acids (13a) and (13b) inhibited heterologous platelet aggregation for 4.5 h. Following intravenous administration in spontaneously hypertensive rats, acids (13a)-(13c) and (14b) lowered the mean blood pressure in a dose dependent manner. At a dose of 100 micrograms/kg, the effect lasted for 20-40 min.

Synthesis and antidepressant profiles of phenyl-substituted 2-amino- and 2-[(alkoxycarbonyl)amino]-1,4,5,6-tetrahydropyrimidines.

A series of 4(6)- and 5-phenyl-substituted 2-amino- and 2-[(alkoxycarbonyl)amino]-1,4,5,6-tetrahydropyrimidines were prepared and evaluated for central nervous system (CNS) effects in animal models. Several 5-phenyl-substituted compounds possessed potent antidepressant activity and all compounds in this series were devoid of significant activity in any of the other CNS (anticonvulsant, muscle relaxant, and depressant) assays. The most active compound in the in vivo screen for antidepressant activity (reversal of reserpine-induced hypothermia), 2-[(methoxycarbonyl)amino]-5-phenyl-1,4,5,6-tetrahydropyrimidine was considerably more potent than tricyclic antidepressant (TCA) standards. The 2-amino parent compound on the other hand was greater than 100-fold as effective as TCA's in in vitro inhibition of norepinephrine and dopamine uptake.

The analgesic and anti-inflammatory profile of ketorolac and its tromethamine salt.

Ketorolac tromethamine[(+/-)-5(benzoyl)-2,3-dihydro-1N-pyrrolizine-1-carboxylic acid tris hydroxymethylaminomethane salt] is a highly potent member of a new class of compounds having analgesic and anti-inflammatory activity. When given orally in tests involving underlying inflammation it was a potent analgesic, whereas it was inactive in tests for narcotic activity. It was also highly active orally in rat models of acute and chronic inflammation and pyresis. These properties are mediated primarily via the compound's potent prostaglandin cyclooxygenase inhibitory activity. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity. A single 10 mg tablet given orally to human volunteers following surgery provided pain relief equivalent to that provided by 10 mg of morphine given intramuscularly. When given intramuscularly to rabbits (0.25 ml of a 0.31-5% solution) or man (3 ml of a 1-3% solution), no drug-related irritation or changes in creatine phosphokinase were seen. Solutions (less than or equal to 0.5%) applied to the eyes of animals and man were not irritating. When applied topically in rat and rabbit models of ocular inflammation, less than or equal to 0.5% solutions of ketorolac tromethamine inhibited the inflammatory response.

Synthesis and central nervous system properties of 2-[(alkoxycarbonyl)amino]-4(5)-phenyl-2-imidazolines.

A series of 2-[( alkoxycarbonyl )amino]-4(5)-phenyl-2-imidazolines was prepared and evaluated for central nervous system (CNS) effects (antidepressant, anticonvulsant, muscle relaxant, and depressant) in animal models. Some separation of those CNS activities was achieved through substitutions on the phenyl and imidazoline moieties. Halo-substituted phenyl compounds were among the most potent antidepressants in this series, while imidazole N-alkylation produced compounds with increased depressant effects (loss of righting reflex, mouse behavior). Comparison of in vitro and in vivo data for pairs of 2-[(methoxycarbonyl)amino]-4(5)-phenyl-2-imidazolines and their parent, 2-amino-4(5)-phenyl-2-imidazolines, suggests that the title compounds were prodrugs for the 2-amino-4(5)-phenyl-2-imidazolines in inhibition of norepinephrine reuptake.

Potentiation of apomorphine-induced gnawing in mice.

1. The association of antagonism of apomorphine-induced climbing with potentiation of apomorphine-induced gnawing in mice has been suggested as a means to detect "atypical" neuroleptics. 2. Clozapine, many compounds with central anticholinergic activity and propranolol have been demonstrated to possess this profile of activities. 3. Pharmacological manipulations with cholinomimetics suggest a cholinergic modulation of the gnawing behavior induced by apomorphine. 4. The observations with propranolol cannot be explained either by a cholinergic link nor by beta-adrenergic antagonism.

The analgesic and anti-inflammatory profile of (+/-)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2a]pyrrole-1-carboxylic acid (RS-37619).

RS-37619 showed highly potent analgesic activity when given p.o. in tests utilizing underlying inflammation. It inhibited phenylquinone-induced writhing in the mouse and rat (350 and 180 x aspirin respectively) and the pain induced by flexing the adjuvant-inflamed rat paw (approximately 800 x aspirin). The agent increased the pain threshold of compressed yeast-inflamed rat paws (3-10 x naproxen). RS-37619 did not increase the pain threshold of the non-inflamed paw and was inactive in the mouse hot plate test; therefore it is probably not a centrally acting or morphine-like agent. RS-37619 was also highly active p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (36 x phenylbutazone), cotton pellet-induced granuloma (less than or equal to 1 x indomethacin) and in an 18-day test, prevented the development of adjuvant-induced arthritis (approximately 2 x naproxen). RS-37619 exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. When given p.o., RS-37619 lowered yeast-induced pyrexia (20 x aspirin). Gastrointestinal irritation was seen in the rat with doses greater than or equal to 6.4 mg/kg/day p.o. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity.

Electrophysiologic studies of a combination of secobarbital and dibucaine for euthanasia of dogs.

A combination of secobarbital and dibucaine was compared with secobarbital and with dibucaine, given IV, for euthanasia of dogs. The secobarbital-dibucaine combination was the most effective, as determined by latency to electrical silence of the EEG and ECG, as well as by visual observation of the behavior of the animal. The combination product produced a quiet and rapid death, according to all electrophysiologic changes that were monitored, whereas the barbiturate resulted in prolonged myocardial activity. Dibucaine alone is not desirable for use for euthanasia.

1-(Naphthylalkyl)-1H-imidazole derivatives, a new class of anticonvulsant agents.

Potent anticonvulsant activity has been demonstrated for a large number of 1-(naphthylalkyl)-1H-imidazoles containing a variety of functional groups in the alkylene bridge. The presence of a small oxygen function in the bridge, in general, confers a high therapeutic index between anticonvulsant and depressant activity. Clinical expectations are discussed for 1-(2-naphthoylmethyl)imidazole hydrochloride (5), which is undergoing development for testing in humans.

The anti-inflammatory and analgesic profile of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (tiopinac).

Tiopinac displayed marked anti-inflammatory activity when given p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (40 x phenylbutazone), and cotton-pellet-induced granuloma (0.8 x indomethacin). In an 18-day test, tiopinac prevented the development of adjuvant-induced arthritis (10-15 x naproxen) and had similar activity versus pre-induced arthritis. Tiopinac exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. Depending upon the type of analgesic test used, the potency of tiopinac varied. When given p.o. it inhibited phenylquinone-induced writhing in the mouse and rat (respectively 16 and 10 x aspirin). In contrast, tiopinac had approximately 10 times the potency of indomethacin in increasing the pain threshold when yeast-inflamed paws were compressed. The pain threshold of the noninflamed paw was not increased. Tiopinac was highly active versus pain induced by flexing the adjuvant arthritic-inflamed paw (greater than or equal to 1000 x aspirin). It was inactive in the mouse hot-plate test in which opiate-like agents are active. Tiopinac, p.o., lowered yeast-induced pyrexia (130 x aspirin). Tiopinac did not have significant cardiovascular or CNS activity. Whereas the Ed50 versus adjuvant arthritis in rats was 0.1 mg/kg/day p.o., rats tolerated up to 20 mg/kg/day p.o. in the 8-day cotton-pellet test. Lack of anorexia and emesis in dogs with up to 30 mg/kg p.o. and mild oral activity in producing gastric erosion in acute and subacute studies in rats suggests that tiopinac may have relatively little gastrointestinal irritating activity.

Synthesis and antiinflammatory activity of 6,11-dihydro-11-oxodibenzo[b,e]thiepinalkanoic acids and related compounds.

Acetic acid derivatives of tricyclic systems, such as 6,11-dihydro-11-oxodibenzo[b,e]thiepin, 4,10-dihydro-4-oxo-thieno[2,3-c][1]benzothiepin, dibenzo[b,f]thiepin, dibenz[b,f]oxepin, etc., were synthesized and assayed for antiinflammatory activity. One of the compounds, 6,11-dihydro-11-oxodibenzo[b,e]thiepin-3-acetic acid (52), was chosen for evaluation in man on the basis of high antiinflammatory activity in both short- and long-term animal assays and a low gastric irritation liability in rats and dogs.

A new anorexigen assay: stress-induced hyperphagia in rats.

Humans often respond to stress by overeating. A rat model of hyperphagia induced by a stressful tail-pinch has been described. Consumption of sweetened condensed milk by vaive rats was measured durin the stress. This milk drinking was prevented by pretreatment with d-amphetamine, chlorphentermine, diethylpropion, fenfluramine, methamphetamine, morphine, chlorpromazine and haloperidol. The benzodiazepines chlordiazepoxide and diazepam increased the hyperphagia. The relevance of dopaminergic agonistic and antagonist activities to anorexigenic activity are questioned.

Cat sleep: a unique first night effect.

Longitudinal sleep studies in chronically implanted cats revealed a unique first night effect. Unlike other species, during the first 24 hr of sleep recording, the electroencephalogram and reticular formation multiple unit activity revealed more rapid eye movement sleep occurred than during subsequent 24 hr recording sessions. In addition, higher rapid eye movement to slow wave sleep ratios were observed for the first 24 hr as compared to the following days. An increase in wakefulness and decrease in slow wave sleep occurred on the third recording day as compared to the initial 24 hr period. These data have important implications for studies of variables on the sleep pattern of animals.

Involvement of biogenic amines in drug-induced aggressive pecking in chicks.

Pairs of neonate chicks were administered psychoactive agents and pecks against each other were recorded during 4-hr test sessions. The first experiment assessed where drug-induced aggressive pecking could serve as a useful anti-depressant screening model. Although pecking was induced by tricyclics, d-amphetamine, and L-Dopa, ineffective agents included a MAO inhibitor (pargline) and a tricyclic indole antidepressant (iprindole). These data cast doubt on the validity of the chick pecking model as a specific antidepressant tests. A second experiment attempted to determine where different amines were involved in pecking induced by an antidepressant and a CNS stimulant. Pairs of chicks were pretreated with various doses of amine antagonists, and a standard dose of imipramine (IMI) or d-amphetamine (AMP) was administered. Haloperidol completely antagonized AMP but not IMI pecking, while phentolamine and propranolol did not modify AMP pecking, suggesting involvement of dopamine. Pecking induced by IMI was partially antagonized by a dose of methysergide ineffective in modifying AMP pecking. Neither phentolamine nor propranolol blocked IMI pecking. Serotonin was further implicated in IMI pecking in a third experiment, whether chronic PCPA pretreatment significantly decreased IMI, but not AMP pecking. These data suggest that aggressive pecking induced by AMP and IMI may be mediated by different amine systems.