Experience with a naphthylmedetomidine-ketamine-hyaluronidase combination in inducing immobilization in anthropoid apes.

BACKGROUND: The aim of the study was to compare the effect of naphthylmedetomidine to medetomidine on the behavior of orangutans and chimpanzees. METHODS: The immobilization was performed as part of a medical examination in five chimpanzees and three orangutans. Following pre-medication with midazolam (0.70-1.20 mg/kg p.o.), naphthylmedetomidine (50-70 microg/kg), or medetomidine (20-30 microg/kg) was given with ketamine (3 mg/kg) and hyaluronidase (150 M.U.) into musculus deltoideus. RESULTS: We observed the distinct anti-aggressive effect of naphthylmedetomidine. The immobilization with naphthylmedetomidine was shallower and the influence on cardiac frequency less substantial compared to medetomidine. The overall sedative effect of naphthylmedetomidine lasted for less time, and its effect was incompletely antagonized with atipamezole in comparison to medetomidine. CONCLUSIONS: Naphthylmedetomidine could replace medetomidine for inducing immobilization and sedation. A combination of naphthylmedetomidine-ketamine is suitable for relocating animals to other cages or for painless medical examinations.

The effect of the novel partial alpha2-adrenoceptor agonist naphthylmedetomidine on the basic cardiorespiratory parameters and behavior in rhesus monkeys.

BACKGROUND: The aim of this study was to compare cardiorespiratory and behavioral profile of a new alpha 2-adrenoceptor ligand naphthylmedetomidine with medetomidine in rhesus monkeys. METHODS: Naphthylmedetomidine or medetomidine (50 microg/kg) together with ketamine (3 mg/kg) and hyaluronidase (150 IU/kg) i.m was administered to 35 rhesus monkeys. Behavioral changes were then observed together with blood pressure, heart rate and oxygen saturation of hemoglobin. RESULTS: The onset of sedation, ataxia, and reduction of aggression was similar in both treatment groups. Immobilization was observed only in medetomidine treated animals, while in naphthylmedetomidine treated animals loss of aggressiveness was observed but the animals never completely lost mobility. Naphthylmedetomidine showed less prominent effects on cardiorespiratory functions compared with medetomidine. CONCLUSIONS: Our results suggest that naphthylmedetomidine can be used to induce sedation in primates and other small animals while avoiding the serious side effects observed after administration of the currently used full alpha(2)-AR agonists.

The effect of the novel alpha-2-adrenoceptor agonist naphthylmedetomidine on pulse rate, arterial blood pressure and sedation in rabbits.

OBJECTIVE: The aim of this study was to investigate the effect of a novel alpha-2-adrenoceptor (alpha(2)-AR) agonist, naphthylmedetomidine, on cardiorespiratory function and sedation in rabbits in comparison with medetomidine. STUDY DESIGN: Prospective, randomized, experimental trial. ANIMALS: Forty-two chinchilla rabbits of both sexes, weighing 2.5-4.5 kg. METHODS: The rabbits received 350 microg kg(-1) naphthylmedetomidine (n = 21) or medetomidine (n = 21) intramuscularly according to a randomization scheme. Arterial blood pressure (AP), oxygen saturation of haemoglobin (SpO(2)), pulse rate (PR) and righting reflex were monitored for 20 minutes after injection. RESULTS: Both drugs significantly decreased PR. The effect of medetomidine was significantly greater than that of naphthylmedetomidine and was evident within 1 minute. The decrease in PR after naphthylmedetomidine administration first appeared after 4 minutes. Medetomidine decreased the SpO(2) after 3 minutes but there was no effect after naphthylmedetomidine. Medetomidine decreased the mean, systolic and diastolic AP within 5 minutes of administration but naphthylmedetomidine had no effect. The mean time to loss of righting reflex was 185 and 714 seconds after the administration of medetomidine and naphthylmedetomidine respectively. CONCLUSIONS AND CLINICAL RELEVANCE: These results provide the first description of the effects of naphthylmedetomidine on cardiovascular and psychomotor functions in rabbits. Further work is required to reveal the anaesthetic sparing, analgesic or sedative effect of partial naphthylmedetomidine.

Selective antiaggressive effect of an alpha-2 adrenoceptor agonist naphthylmedetomidine in mice.

Alpha-2 adrenoceptors (alpha(2)-ARs) are critically involved in regulating neurotransmitter release from sympathetic nerves and neurons and play an important role in the regulation of awareness, arousal and vigilance. In our recent study, dexmedetomidine, a full alpha(2)-AR agonist, produced antiaggressive effects in the social conflict test in mice at doses that were twice smaller than those producing sedation. The aim of this study was to ascertain antiaggressive effect of a novel drug naphthylmedetomidine, with a more selective alpha(2)-AR activity. Behavioral effects of naphthylmedetomidine (150-1200 microg/kg i.p.) were studied in the activity cage and in the social conflict tests in mice. Naphthylmedetomidine dose dependently decreased aggressive behavior during social conflict in aggressive mice with significant reduction already at the lowest doses tested (150 microg/kg), whereas locomotion and social investigation were significantly decreased only after four times bigger dose of naphthylmedetomidine (600 microg/kg) in aggressive mice. Naphthylmedetomidine had no effect on aggression in nonaggressive mice. Naphthylmedetomidine reduced locomotion in the activity cage significantly only at the highest doses tested (600 and 1200 microg/kg), and this effect was only partially reversed by administration of high doses of an alpha-2 antagonist atipamezole (3 and 10 mg/kg). In nonaggressive mice, the difference between the dose reducing dominant social behavior (social investigation) and locomotion (150 and 300 microg/kg, respectively) was smaller than in aggressive mice. In conclusion, naphthylmedetomidine showed a very strong and selective antiaggressive effect in aggressive mice, which was devoid of locomotion-inhibiting/sedative effect. This study suggests that naphthylmedetomidine may have clinical potential as antiaggressive drug.

Medetomidine analogs as selective agonists for the human alpha2-adrenoceptors.

alpha(2)-Adrenoceptor (AR) agonists have therapeutic applications in a variety of diseases. Medetomidine, an alpha(2)-AR agonist, belongs to 4-substituted imidazole class of compounds and is highly selective for the alpha(2)-AR. The benzylic methyl group of medetomidine and naphthalene imidazole was proposed to interact with rat brain alpha(2)-ARs via a methyl binding pocket in a manner analogous to its presence in alpha-methyl norepinephrine. A series of derivatives containing hydrophilic and hydrophobic substituents, as well as chiral and conformationally rigid analogs were used. In current binding and functional studies using human alpha(2)-AR subtypes expressed in Chinese hamster ovary cells, optimal interactions were observed with the presence of the methyl group on the benzylic carbon atom of naphthyl imidazole. Data obtained with various analogs have demonstrated that size, electronegativity, lipophilicity, chirality and conformational flexibility of the substituents at the carbon bridge of naphthyl imidazole are important factors for interaction of the imidazole class of ligands with these alpha(2)-AR subtypes. Taken collectively, the results obtained support the existence of the methyl binding pocket for optimal ligand receptor binding interactions in human alpha(2)-AR subtypes. Further, the results also suggest that, additional modifications of medetomidine and naphthyl methyl imidazole at the benzylic carbon atom, and/or on the aromatic and imidazole ring systems could provide insights into the chemical requirements for optimizing alpha(2)-AR subtype selectivity. This could eventually lead to the discovery of promising compounds for the evaluation of the physiological importance of the three alpha(2)-AR subtypes.

A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic receptors.

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.

Resolution and adrenergic activities of the optical isomers of 4-[1-(1-naphthyl)ethyl]-1H-imidazole.

Recently we synthesized a naphthalene analog of medetomidine, 4-[1-(1-naphthyl)ethyl]-1H-imidazole hydrochloride (1), and found it to be highly potent in adrenergic systems. The separation of optical isomers of this naphthalene analog was achieved by using the isomers of tartaric acid. The optical purities of the isomers were determined by HPLC using a chiral column. Using X-ray analysis the (+)-isomer was determined to have the S absolute configuration. It has been reported that the (+)-isomer of medetomidine (2) is the most potent enantiomer on alpha 2-adrenergic receptors. There were both qualitative and quantitative differences in biological activities of the optical isomers of 1 in alpha 1- and alpha 2-adrenergic receptor systems of guinea pig ileum and human platelets. (+)-(S)-1, but not (-)-(R)-1 was a selective agonist of alpha 2-mediated responses in ileum whereas (-)-(R)-1 was more potent than (+)-(S)-1 as an inhibitor of alpha 2-mediated platelet aggregation.