摘要:

AbstractThe discovery of drugs (and their subsequent development) is a difficult subspeciality in pharmacology that, in conjunction with clinical medicine, generates the vitality underlying the entire pharmacologic‐therapeutic enterprise. The drug discovery process is unique among biomedical sciences in that it takes place almost solely in industrial research institutions rather than in nonindustrial institutions—i.e., academic and government laboratories. The conventional view of drug discovery is that, since it is mission‐oriented and pharmacological, it is derivative on the basic pharmacological research carried out in nonindustrial research institutions. It is argued by the author that this model is oversimplistic and is not applicable to pharmaceutical research: It is very frequently the case that drugs are developed first and thus precede “basic” knowledge and in fact are the source of new academic findings, especially in pharmacology. In addition, new drugs are useful tools in physiology and biochemistry. Thus, the discovery of an innovative drug is per se a basic contribution. A more reasonable model of the relationship between drug discovery (and development) and nonindustrial research—physiological, biochemical, and pharmacological—is that of symbiosis with each segment nurturing the other to mutual benefit.The problems of pharmacologists involved in drug development are more complex than those of nonindustrial pharmacologists in that the end points of their work—successful clinical trial and marketing—demand more than an interesting pharmacological action; the action must be of therapeutic significance and be resident in a molecule which has been determined to be nontoxic, bioavailable, patentable, and commercially viable. The differences in goals between academic (non‐mission‐oriented) and industrial (mission‐oriented) pharmacological research and the consequent demands in the latter for specified kinds of results often leads to differing patterns of research and research judgments that can be a source of misunderstandings and confusion between industrial and nonind

ISSN:0272-4391    

DOI:10.1002/ddr.430040402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractAY‐27,110 is the pharmacologically active enantiomer of a troponylpiperazine derivative. At low doses, the compound induced contralateral rotational behavior in rats with a unilateral 6‐OHDA lesion of the nigrostriatal pathway, at higher doses it caused weak stereotypy and in dogs in elicited emesis. The actions of AY‐27,110 were dose‐dependently antagonized by haloperidol and pimozide, but were not diminished by α‐MPT or reserpine pretreatment. These results indicate that AY‐27,110 is a chemically novel dopaminergic agonist that should be useful as an anti‐parkinson drug. Since the effects of AY‐27,110 are independent of intact catecholamine synthesis and storage mechanisms, the compound should be efficacious in patients with advanced Parkinson's disease. AY‐27,110 was compared to several ergot‐derived dopamine agonists, namely bromocriptine, lisuride, and pergolide, in order to predict its potency, side‐effect liability, and potential

ISSN:0272-4391    

DOI:10.1002/ddr.430040403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractTHIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol), a structurally rigid analog of the GABA‐agonist muscimol, was investigated for antinociceptive activity in a variety of preclinical tests for analgesic activity. Antinociceptive activity was observed in the mouse writhing, mouse hot plate, rat tail flick, rat inflamed paw, and monkey shock titration tests. In the mouse writhing, mouse hot plate, and rat tail jerk experiments, periods of significant hyperalgesia were noted either prior to or following the occurrence of THIP‐induced antinociception. At those times when an antinociceptive effect of THIP could be demonstrated in the test systems employed in this study, a variety of unfavorable effects were noted including sedation, ataxia, myoclonic jerks, and vomiting. These side‐effects of THIP first appeared near the dose that produced antinociception in 50% of the animals (ED50value) and became progressively more intense as the dose increased. Neither the narcotic antagonist naloxone, the cholinergic antagonist atropine, nor the GABA‐antagonists bicuculline or picrotoxin blocked the antinociceptive activity of THIP. The synthesis of prostaglandins was not inhibited by THIP. The antinociceptive activity of THIP is an interesting lead in the search for a novel analgesic that lacks the undesirable effects of opiates. However, the occurrence of hyperalgesia and marked side‐effects at doses near the effective analgesic dose may limit THIP's ther

ISSN:0272-4391    

DOI:10.1002/ddr.430040404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractRepresentative compounds from a series of phenylpiperidine‐opioid antagonists were compared in their ability to antagonize the diuretic effect of 0.08 mg/kg of bremazocine, a kappa‐opioid receptor agonist. Three of the compounds produced dose‐related antagonism of bremazocine, whereas four others did not. The four ineffective compounds also did not exhibit any kappa agonist activity. The potency of the three effective antagonists did not correlated with their antagonist activity against morphine or in suppressing deprivation‐induced drinking. These results demonstrate that several kappa receptor antagonists can be found in the phenylpiperidine series of opioid antagonists, and further emphasize the usefulness of kappa‐mediated diuresis as an in vivo test for kappa‐opioid recept

ISSN:0272-4391    

DOI:10.1002/ddr.430040405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractDespite a unique in vivo pharmacology,Kagonists possess moderate to high affinities for μ, δ, and κ binding sites in vitro. By monitoring the antagonist activity of κ agents on morphine‐ and DADLE‐dependent changes in dopamine and acetylcholine metabolism we were able to demonstrate a specific μ2and δ receptor antagonism for κ analgesics. Furthermore, this antagonism was probably directly at the receptor level and not phy

ISSN:0272-4391    

DOI:10.1002/ddr.430040406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430040407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430040401

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY