Biomedical subjects

Anil H Vaidya

Publications and source records attributed to Anil H Vaidya.

6 recordsLinked to original sources

PubMed2007

Effects of atypical anxiolytic N-phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) on alcohol intake in alcohol-preferring P rats.

BACKGROUND: N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) is a structurally novel atypical anxiolytic with an overall in vivo profile in animals suggestive of the potential to show anxiolytic efficacy in humans at doses that will not cause CNS-related side effects. Furthermore, unlike the benzodiazepines, JNJ-5234801 does not have an adverse interaction with ethanol even at doses 20 to 40 times the minimal effective dose in the rat elevated plus maze (MED=1.0 mg/kg, p.o.). METHODS: In the present study, JNJ-5234801 was evaluated for potential efficacy in reducing alcohol intake in alcohol-preferring rats. Alcohol-preferring P rats were allowed to drink water or alcohol (10%, v/v) in a 2-bottle choice procedure. Once stable baselines were established, the acute effects of JNJ-5234801 [(10-40 mg/kg, intraperitoneally (i.p.)] were assessed. In a separate study, chronic treatment with JNJ-5234801 (40 mg/kg once daily, i.p.) for 12 consecutive days was compared with naltrexone (20 mg/kg, twice daily, i.p.). RESULTS: There was a selective dose-dependent reduction in alcohol intake in the alcohol-preferring (P) rats after acute administration of JNJ-5234801 (10-40 mg/kg, i.p.). There were no significant effects on food or water intake. When administered subchronically, both JNJ-5234801 (40 mg/kg once daily, i.p.) and naltrexone (20 mg/kg, twice daily, i.p.) considerably reduced alcohol intake, but tolerance to the alcohol-suppressing effects appeared to occur sooner in the naltrexone-treated group. While both compounds slightly but significantly reduced food intake at the beginning, only JNJ-5234801 increased water intake and decreased alcohol preference. CONCLUSIONS: The novel atypical anxiolytic JNJ-5234801 has a favorable profile effects on alcohol intake and related measures compared with naltrexone, which is recommended for the treatment of alcoholism.

Acute Disease↗

PubMed2006

Diarylacetylene piperidinyl amides as novel anxiolytics.

N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (9) and related piperidine acetamide derivatives have good oral activity in the elevated plus maze, an animal model predictive of clinical efficacy for the treatment of anxiety. Modest affinity was observed for the neurokinin NK-1 and 2 receptors, which are known to be involved in the regulation of mood and emotion.

Acetylene↗

PubMed2003

2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats.

The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on (125)I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC(50). When delivered intraperitoneally, compounds 3a, 3b, and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.

Animals↗

PubMed2003

Virus-based expression systems facilitate rapid target in vivo functionality validation and high-throughput screening.

Target validation is one of rate-limiting steps in the modern drug discovery. The authors developed a strategy of combining adenovirus-mediated gene transfer for efficient target functionality validation, both in vivo and in vitro, with baculovirus expression to produce sufficient quantities of protein for high-throughput screening (HTS). The incorporation of green fluorescent protein (GFP) in the adenovirus vectors accelerates recombinant adenovirus plaque purification, whereas the use of epitope and affinity tags facilitates the identification and purification of recombinant protein. In this generalized scheme, the flexible modular design of viral vectors facilitates the transition between target validation and HTS. In the example presented, functional target validation in vivo was achieved by overexpressing the target gene in cell-based models and in the mouse cortex following adenovirus-mediated gene delivery. In this context, target overexpression resulted in the accumulation of a disease-related biomarker both in vitro and in vivo. A baculovirus-based expressional system was then generated to produce enough target protein for HTS. Thus, the use of these viral expression systems represents a generalized method for rapid target functionality validation and HTS assay development, which could be applied to numerous target candidates being elucidated in gene discovery programs.

Adenoviridae↗

PubMed2002

Potential anxiolytic agents. Part 4: novel orally-active N(5)-substituted pyrido[1,2-a]benzimidazoles with high GABA-A receptor affinity.

A series of pyrido[1,2-a]benzimidazoles (PBIs) with substitution on the N(5)-nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24, which has an IC(50) of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials.

Administration, Oral↗

PubMed2002

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2a]pyridine-4-N-(2-fluorophenyl)carboxamide (RWJ-51204), a new nonbenzodiazepine anxiolytic.

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5] imidazo[1,2a]pyridine-4-N-(2-fluorophenyl)carboxamide) (RWJ-51204) binds selectively and with high affinity (K(i) = 0.2-2 nM) to the benzodiazepine site on GABA(A) receptors. Considering the GABA shift, the intrinsic modulatory activity of RWJ-51204 is lower than that of full agonist anxiolytics (lorazepam, diazepam, alprazolam, and clonazepam) but similar to partial agonists (bretazenil, abecarnil, panadiplon, and imidazenil). RWJ-51204 was orally active in anxiolytic efficacy tests; pentylenetetrazole induced seizure inhibition in mice (ED(50) = 0.04 mg/kg), Vogel conflict in rats (ED(50) = 0.36 mg/kg), elevated plus-maze in rats (minimal effective dose = 0.1 mg/kg), and conflict in squirrel monkeys (ED(50) = 0.49 mg/kg). RWJ-51204 attenuated chlordiazepoxide-induced motor impairment in mice. Usually, RWJ-51204 was more potent than reference anxiolytics in rodent efficacy tests but less potent in monkey conflict. Usually, the slope of the dose-response lines for RWJ-51204 was more shallow than the full agonist anxiolytics but steeper than partial agonists in efficacy tests but typically shallow in tests for central nervous system side effects. In monkeys only mild or moderate sedation was observed at doses equivalent to 20 or 40 times the anxiolytic ED(50). RWJ-51204 fits into the partial agonist class of GABA(A) receptor modulators. In conclusion, RWJ-51204 exhibits a profile in in vitro experiments and in animal models, in mice and monkeys (but not in rats), suggesting that it has a profile of anxiolytic activity associated with less sedation, motor impairment, or muscle relaxation than currently available GABA(A) receptor modulators, i.e., the benzodiazepines.

Animals↗