The novel, orally active, delta opioid RWJ-394674 is biotransformed to the potent mu opioid RWJ-413216.

Although the mu opioid receptor is the primary target of marketed opioid analgesics, several studies suggest the advantageous effect of combinations of mu and delta opioids. The novel compound RWJ-394674 [N,N-diethyl-4-[(8-phenethyl-8-azabicyclo]3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide]; bound with high affinity to the delta opioid receptor (0.2 nM) and with weaker affinity to the mu opioid receptor (72 nM). 5'-O-(3-[(35)S]-thio)triphosphate binding assay demonstrated its delta agonist function. Surprisingly given this pharmacologic profile, RWJ-394674 exhibited potent oral antinociception (ED(50) = 10.5 micromol/kg or 5 mg/kg) in the mouse hot-plate (48 degrees C) test and produced a moderate Straub tail. Antagonist studies in the more stringent 55 degrees C hot-plate test demonstrated the antinociception produced by RWJ-394674 to be sensitive to the nonselective opioid antagonist naloxone as well as to the delta- and mu-selective antagonists, naltrindole and beta-funaltrexamine, respectively. In vitro studies demonstrated that RWJ-394674 was metabolized by hepatic microsomes to its N-desethyl analog, RWJ-413216 [N-ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide], which, in contrast to RWJ-394674, had a high affinity for the mu rather than the delta opioid receptor and was an agonist at both. Pharmacokinetic studies in the rat revealed that oral administration of RWJ-394674 rapidly gave rise to detectable plasma levels of RWJ-413216, which reached levels equivalent to those of RWJ-394674 by 1 h. RWJ-413216 itself demonstrated a potent oral antinociceptive effect. Thus, RWJ-394674 is a delta opioid receptor agonist that appears to augment its antinociceptive effect through biotransformation to a novel mu opioid receptor-selective agonist.

In vitro metabolism of the analgesic agent, RWJ-37874, in rat and human.

RWJ-37874, an analogue of aroyl(aminoacyl)pyrrole, is a new analgesic agent. The in vitro metabolism of RWJ-37874 was conducted using rat and human hepatic S9 in the presence of an NADPH generating system, and API-ionspray-MS and MS/MS techniques for metabolite profiling and identification. Unchanged RWJ-37874 (66 & 86% of the sample in rat & human, respectively) plus four metabolites were profiled and tentatively identified on the basis of MS data. RWJ-37874 metabolites were formed via the following two metabolic pathways: 1. oxidative N-deethylation, and 2. pyrrole-oxidation. Pathway 1 produced a mayor and a minor metabolites, N-desethyl-RWJ-37874 (M1; 34% in rat; 13% in human) and N,N-didesethyl-RWJ-37874 (M3; <0.5% in both species), respectively. Pathway 2 formed hydroxypyrrole-RWJ-37874 (M2; <0.5% in all species), and in conjunction with step 1, formed hydroxy-M1 (M4; <0.5% in rat). RWJ-37874 is substantially metabolized in rat and human hepatic S9 fractions. However, rat appears to metabolize RWJ-37874 more extensively than human via N-dealkylation forming N-desethyl-RWJ-37874 as a major metabolite.

In vitro biotransformation of the analgesic agent, RWJ-51784, in rat, dog and human.

RWJ-51784, an analogue of phenyl isoindoles, is a new analgesic agent. The in vitro metabolism of RWJ-51784 was conducted using rat, dog and human hepatic S9 in the presence of an NADPH generating system, and API-ionspray-MS and MS/MS techniques for the metabolite profiling and identification. Unchanged RWJ-51784 (82, 80 & 86% of the sample in rat, dog & human, respectively) plus 6 metabolites were profiled and tentatively identified on the basis of MS data. RWJ-51784 metabolites were formed via the following 3 metabolic pathways: 1. N-demethylation, 2. phenylhydroxylation, and 3. isoindole-oxidation. Pathway 1 produced a moderate or minor metabolite, N-desmethyl-RWJ-51784 (M1; 6% in rat; 5% in dog, 2% in human). Pathway 2 formed 4-hydroxyphenyl-RWJ-51784 (M2; 3-6% in all species). Step 3 formed 2 isoindole-oxidized metaboliotes, OH-indole (M3; 7-8% in all species) and oxo-indole (M4; <1% in all species)-RWJ-51784, and in conjunction with pathway 2 produced 2 trace metabolites, OH-phenyl-OH-isoindole (M5) and OH-phenyl-oxo-isoindole (M6) metabolites. RWJ-51784 is not extensively metabolized in rat, dog and human hepatic S9 fractions.

Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor: a combined 3D-QSAR and ligand docking study.

A series of 4-(N,N-diarylamino)piperidines are synthesized and evaluated for high affinity binding and selectivity to the delta-opioid receptor using a combination of 3D-QSAR and molecular docking techniques. Based on experimental ligand binding data to both mu- and delta- opioid receptors, CoMFA fields are generated and applied to identify potential ligand modifications to further optimize lead compounds. Molecular docking experiments to the delta-receptor are also reported that explain the CoMFA trends predicted as well as the differential binding and selectivity displayed by various compounds in the series. An analysis of the binding site model proposed indicates the piperidines take advantage of 3 key sites or binding domains within the delta-receptor. These include an aromatic pocket (approximately 1/3 into the receptor cavity), an aspartic acid residue (which serves as a docking point for the piperidinyl cationic amine) and a hydrophobic pocket at the extracellular boundary of the receptor cavity. Links are established between ligand modification and amino acid composition at these sites in mu and delta, providing new insight to the structural basis to binding and selectivity across the series and for related piperazines (i.e. SNC80 and BW373U86). Results are also presented that indicate delta- and mu-selectivity may be determined at alternate sites, suggesting opioid receptors may display multiple binding domains. The model is further supported by comparisons with opiate binding modes and site directed mutagenesis studies and is finally applied to suggest new strategies in ligand design.

Synthesis and binding affinities of 4-diarylaminotropanes, a new class of delta opioid agonists.

A series of 4-diarylaminotropanes has been prepared. Both endo and exo diastereomeric forms bound to the delta opioid receptor but the endo isomers were more potent and selective versus the mu opioid receptor than the exo isomers. The most potent delta opioid agonist (14) exhibited a delta opioid Ki of 0.2 nM and was 860-fold selective over mu.

Excretion and metabolism of the antihypertensive agent, RWJ-26240 (McN-5691) in dogs.

The excretion and metabolism of a 2-ethynylbenzenealkanamine analog, antihypertensive RWJ-26240 (McN-5691), in beagle dogs was investigated. Recoveries of total radioactivity in urine and feces in the 7 days after oral administration of 14C-RWJ-26240 (6 mg/kg dose) were 2.8% and 96.8% of the radioactive dose, respectively. Representative plasma, urine, and fecal samples were pooled and purified for metabolite profiling, isolation, and identification. Unchanged RWJ-26240 (<19% of the dose) plus 12 metabolites were isolated and identified from these samples using chromatography (TLC, HPLC), spectroscopy (NMR, MS), and derivatization techniques. Unchanged RWJ-26240 plus identified metabolites accounted for >75% of the sample radioactivity in plasma and feces. The formation of RWJ-26240 metabolites can be depicted by the following proposed pathways: 1) N-demethylation, 2) O-demethylation, 3) phenyl hydroxylation, and 4) N-dealkylation. The first three pathways appeared to be quantitatively important steps which led to the production of four major metabolites (each >5% of the sample radioactivity). RWJ-26240 was extensively metabolized in the dog, and fecal excretion was the major route of elimination of RWJ-26240 and its metabolites.

Aroyl(aminoacyl)pyrroles, a new class of anticonvulsant agents.

2-Aroyl-4-(omega-aminoacyl)- (4) and 4-aroyl-2-(omega-aminoacyl)pyrroles (9) represent a new, structurally novel class of anticonvulsant agents. Compounds of type 4 were prepared by Friedel-Crafts acylation of a 2-aroylpyrrole with an omega-chloroacyl chloride followed by displacement of the chloro group by a primary or secondary amine. Compounds of type 9 were prepared by Friedel-Crafts aroylation of a 2-(omega-chloroacyl)pyrrole followed by displacement by an amine. These compounds were active in the mouse and rat maximal electroshock tests but not in the mouse metrazole test. The lead compound, RWJ-37868, 2-(4-chlorobenzoyl)-4-(1-piperidinyl-acetyl)-1,3,5-trimethylpyrrole++ + (4d), showed potency and therapeutic index comparable to those of phenytoin and carbamazepine and greater than those of sodium valproate. This compound blocked bicuculline induced seizures, did not elevate seizure threshold following iv infusion of metrazole, and blocked influx of Ca2+ ions into cerebellar granule cells induced by K+ or veratridine.

2-Substituted 1-azabicycloalkanes, a new class of non-opiate antinociceptive agents.

2-Substituted 1-azabicycloalkanes (3- and 5-aryloctahydroindolizines 2 and 11, 3-cyclohexyloctahydroindolizine 12, 4-aryloctahydroquinolizines 13, and 3-arylhexahydropyrrolizines 14) constitute a new class of non-opiate antinociceptive agents. These compounds demonstrated activity in the mouse abdominal constriction test and many were active in the mouse tail-flick test. trans-3-(2-Bromophenyl)octahydroindolizine (2a) did not bind to the opiate receptor nor did it affect arachidonate metabolism. 3-Aryloctahydroindolizines were prepared by catalytic hydrogenation of 1-aryl-3-(2-pyridinyl)-2-propen-1-ones. The X-ray crystal structure of (-)-2a was determined and absolute stereochemistry assigned as 3-R,8a-R.

Structurally novel antihypertensive compound, McN-5691, is a calcium channel blocker in vascular smooth muscle.

These studies were conducted to gain greater understanding of the mechanism of action of the chemically novel antihypertensive agent, McN-5691. McN-5691 (1 and 10 microM) prevented 60 mM KCl-induced contraction and calcium uptake and caused concentration-dependent relaxation (EC50 = 190 microM) of 30 mM KCl-contracted aortic rings. At or below 10 microM, McN-5691 had no effects on basal tone or calcium uptake (45Ca) in isolated rings of rabbit thoracic aorta. McN-5691 caused complete high affinity inhibition (Kd = 39.5 nM) of specific diltiazem binding to the benzothiazepine receptor on the voltage-sensitive calcium channel in skeletal muscle microsomal membranes. In contrast to diltiazem, McN-5691 inhibited specific dihydropyridine receptor binding, but the effect was biphasic with high (Kd = 4.7 nM) and low (Kd = 919.8 nM) affinity components. These findings suggest that McN-5691 is a voltage-sensitive calcium channel blocker. Unlike other calcium channel blockers, McN-5691 inhibited norepinephrine (NE)-induced contraction (10 microM) and calcium uptake (1 and 10 microM) and caused concentration-dependent relaxation (EC50 = 159 microM) of 1 microM NE-contracted rings of rabbit thoracic aorta. The vascular relaxant effects of McN-5691 were not related to increased calcium (45Ca) efflux from vascular smooth muscle cells. The effects of McN-5691 on NE-induced contraction were unrelated to intracellular mechanisms because McN-5691 did not affect NE-induced contraction in the absence of extracellular calcium. McN-5691 had weak activity in rat cerebral cortical membrane alpha-1 or alpha-2 adrenergic receptor binding assays. McN-5691-induced vasodilation of phenylephrine-contracted rat aortic strips was not reversible by high potassium, indicating that McN-5691 does not induce relaxation of blood vessels through potassium channel activation. In summary, these studies suggest that the primary vasodilator mechanism of McN-5691 is calcium channel blockade through competitive binding at the diltiazem site on the voltage sensitive calcium channel. McN-5691 may possess an additional vasodilator mechanism of action distinct from alpha adrenergic receptor blockade but involving a cell membrane-related event apparently leading to attenuation of receptor-operated calcium channel activity.

Antinociceptive action of McN-5195 in rodents: a structurally novel (indolizine) analgesic with a nonopioid mechanism of action.

McN-5195 [(+/-)-trans-3-(2-bromophenyl)-octahydroindolizine] inhibited at nontoxic doses the nociceptive response in tail-pinch, tail-flick and 48 degrees C hot-plate tests of mice, with ED50 values of 38.2, 33.9 and 30.9 mg/kg i.p., respectively, and of rats, with ED50 values (i.p.) of 33.2 mg/kg (tail-flick) and 33.3 mg/kg (hot-plate). The compound was p.o. active in the acetylcholine-induced irritant test (ED50 = 20.1 mg/kg) in mice and the air-induced irritant test (ED50 = 33.2 mg/kg) in rats. McN-5195 blocked thalamic activity (multiunit recordings from the ventral posterolateral nucleus) evoked by noxious stimulation of the contralateral hindlimb of anesthetized rats, but did not alter thalamic activity during non-noxious stimulation. The antinociceptive action of McN-5195 was not blocked by naloxone and was not diminished in morphine-tolerant animals. McN-5195 did not affect arachidonate metabolism and was not active against carrageenan-induced paw edema or in an adjuvant arthritis test in rats. McN-5195 did not bind to opiate, serotonin S1 or S2, dopamine D2, alpha-1, alpha-2, beta adrenergic or gamma-aminobutyric acid-A receptors and did not inhibit the synaptic uptake of norepinephrine, serotonin, dopamine or gamma-aminobutyric acid. McN-5195-induced antinociception was not affected by reserpine or phentolamine pretreatment and was not reduced in clonidine-tolerant animals. Ketanserin and yohimbine inhibited McN-5195-induced antinociception by an indirect mechanism. Tolerance did not develop to chronic administration of McN-5195 (120 mg/kg 3 times per day for 10 days). We conclude that McN-5195 is a structurally novel (indolizine) antinociceptive agent that produces its analgesic action via a nonopioid mechanism, not involving products of arachidonate metabolism.

Effects of the novel coronary selective calcium channel blocker, McN-6186, on cardiocirculatory dynamics, coronary vascular resistance, and cardiac output distribution in normal, conscious rats.

The purpose of this study was to characterize the cardiocirculatory effects of the novel calcium channel blocker, McN-6186 (McN), normal, conscious rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive microsphere technique was used to measure regional blood flow (RBF) and cardiac output (CO) before (control) and during intravenous (i.v.) infusion of either McN at three doses (0.03, 0.1, 0.3 mg/kg) or vehicle at an equal infusion rate (0.0408 ml/min). Nifedipine (NIF) was also studied at three similar blood pressure (BP)-lowering doses (0.025, 0.150, and 0.375 mg/kg). The predominant effect of McN in conscious rats was to cause coronary vasodilation. The coronary vasodilator potency of McN was similar to NIF (ED25, McN = 0.03 mg/kg, NIF = 0.025 mg/kg). Neither McN nor NIF significantly changed systemic vascular resistance (SVR) over their respective coronary vasodilator dose ranges, suggesting that both compounds are selective coronary vasodilators. The doses of McN and NIF that reduced mean arterial pressure (MAP) by 25% (ED25) were similar (McN = 0.3 mg/kg, NIF = 0.375 mg/kg). At equal BP-lowering doses, McN increased coronary flow by 145% versus 110% for NIF. McN did not have major effects on other regions of the peripheral circulation. There was, however, some vasodilator activity in the renal and cerebral vascular beds. Because McN reduced coronary vascular resistance at a dose lower than that required to reduce resistance in other vascular beds, this compound appears to be a selective coronary vasodilator and may have therapeutic efficacy as an antianginal agent.

Genetic toxicity of a pharmacologically active group of ortho-(arylalkynyl)phenoxypropanolamines.

A series of ortho-(arylalkynyl)phenoxypropanolamines with antihypertensive activity in laboratory animals was screened in vitro for mutagenicity using the Ames test and the mouse lymphoma assay, and for DNA damaging potential in the primary rat hepatocyte/DNA repair assay. Those compounds with a dialkylamino group on the para position of the arylalkynyl function were shown to be genotoxic in both mutagenicity assays when tested in the presence of an Aroclor 1254-induced rat liver S-9 mix. They were also active in the DNA repair assay. Removal of the para-dialkylamino group or changing the position of this group on the aryl ring eliminated the genotoxic effect in these test systems. This collaborative effort between chemists, pharmacologists, and toxicologists successfully identified the structural feature responsible for the genotoxic activity and indicated structural alterations that would yield a pharmacologically active compound with no genotoxicity in these in vitro assays.

Effects of the novel calcium channel blocker, McN-5691, on cardiocirculatory dynamics and cardiac output distribution in conscious spontaneously hypertensive rat.

The purpose of this study was to characterize the cardiocirculatory effects of McN-5691 in the conscious spontaneously hypertensive rat (SHR) and in age matched Wistar-Kyoto (WKY) control rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular arterial, and venous pressure recordings. The radioactive microsphere technique was used to estimate regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either McN-5691 at three dosage levels (0.3, 1.0, 3.0 mg/kg), or vehicle (VH) at an infusion rate of 0.0408 ml/min. The predominant hemodynamic effect of McN-5691 (cumulative dose = 0.3-4.3 mg/kg i.v.) in conscious SHR was dose-related reduction in mean arterial pressure with normalization occurring at a cumulative dose of 1.3 mg/kg i.v. The antihypertensive effect of McN-5691 was accompanied by reductions in left ventricular peak systolic pressure (cumulative dose = 1.0-4.3 mg/kg i.v.), arterial pressure-rate product (1.3-4.3 mg/kg i.v.), and systemic vascular resistance (4.3 mg/kg i.v.). McN-5691 had no statistically significant effect on heart rate or cardiac contractility as measured by dP/dt/peak left ventricular pressure. The predominant peripheral vascular effects of McN-5691 were increases in skeletal muscle blood flow (4.3 mg/kg i.v.) and reductions in skeletal muscle (1.3-4.3 mg/kg i.v.), renal (1.3-4.3 mg/kg i.v.), gastrointestinal (4.3 mg/kg i.v.), and coronary (1.3-4.3 mg/kg i.v.) vascular resistances. Despite the fall in renal vascular resistance, renal blood flow was not changed by McN-5691. McN-5691 did not have major effects on other regions of the peripheral circulation. Thus, McN-5691 is an antihypertensive agent as defined by its ability to normalize blood pressure in the SHR, and the hemodynamic mechanism leading to this effect is reduction in peripheral vascular resistance. This antihypertensive effect is not accompanied by reflex tachycardia and is not associated with negative inotropic activity or detrimental peripheral circulatory changes in the conscious SHR.

2-Ethynylbenzenealkanamines. A new class of calcium entry blockers.

A series of 2-(aryl- or alkylethynyl)benzenealkanamines were synthesized. They exhibit antihypertensive activity in spontaneously hypertensive rats and coronary vasodilator activity with minimal negative inotropic activity in the "Langendorff" guinea pig heart in vitro. They have been shown to exert their activity by inhibition of Ca2+ influx across cell membranes. Optimal activity is found among the N-(arylethyl)-5-methoxy-alpha-methyl-2-(phenylethynyl)ben zeneethanamines and -propanamines.

Effect of thiouracil on response to heat stress of White Leghorn lines selected for fast and slow gain in two temperatures.

Four lines of White Leghorns previously selected for fast and slow gain from 5 to 9 weeks of age in a hot (32.2 C) and in a cold (21.1 C) selection environment were grown from 5 to 9 weeks in the same two temperature environments. Samples of 32 females from each line of the third generation grown in each temperature environment from 5 to 9 weeks of age were divided into two groups; one received .2% thiouracil in the diet for a 5-day period and the other did not. The temperature was then increased to 40.6 C until 52.8% of all birds had died. The percentages of mortality of lines, rearing environments, and thiouracil treatments were then analyzed. An increase of 64.8% mortality from acute heat stress for birds reared in the cold environment was significant, but the differences among the four selected lines were not. The presence of thiouracil in the diet significantly reduced mortality from heat stress by 16.4%. There were no significant interactions between thiouracil treatments and selected lines or rearing environments.

Performance at two rearing temperatures of White Leghorn lines selected for increased and decreased survival under heat stress.

Body weight and percent mortality resulting from heat stress at 40.6 C were determined on two lines selected for resistance and susceptibility to heat stress by the Florida Agricultural Experiment Station and reared from 5 to 9 weeks of age in two temperatures, 32.2 C and 21.1 C. The resistant line was significantly smaller in body weight at 5 and 9 weeks of age and had less gain in weight from 5 to 9 weeks of age than the heat susceptible line. Birds reared in the cold environment had significantly larger 9-week body weight and gain from 5 to 9 weeks of age than those reared in the hot environment. At 9 weeks of age the birds were heat stressed at 40.6 C and 50% relative humidity. The heat resistant line had a significantly lower percent mortality than the heat susceptible line. Birds reared at 21.1 C had a significantly greater percent mortality when heat stressed than those reared at 32.2 C. No interaction occurred between the selected lines and the temperatures in which they were reared for percent mortality or any of the body weight traits. Comparison with other experiments involving the same base population from which the Florida lines were selected indicated that the response to selection for resistance was greater than that to selection for susceptibility. It is suggested that natural selection for heat resistance could be responsible for the asymmetry of response. An estimate of the genetic correlations (rG) was derived as the geometric mean of the ratios of correlated to direct responses. The estimate of rG between body weight gain from 5 to 9 weeks of age and percent mortality under heat stress was .16.

Survival under heat stress of lines selected for fast and slow growth at two temperatures.

Two replicates of four lines of White Leghorn chickens previously selected for fast and slow gain from 5 to 9 weeks of age in a hot (32.2 C) and cold (21.1 C) selection environment were grown from 5 to 9 weeks in the hot and cold temperature environments and then subjected to high temperature stress at 40.6 C. Four different experiments were run. The percent mortality was analyzed when approximately 50% of the birds had died. Birds reared in the cold environment were heavier and consistently had higher mortality than those reared in the hot environment when both were subjected to acute heat stress (40.6 C). The importance of acclimation to mild heat stress on response to acute heat stress was demonstrated by the mortality difference. No significant differences in survival under heat stress were found between lines selected in the hot and the cold selection environments. Lines selected for fast growth had significantly higher mortality rates under high temperature stress than lines selected for slow growth in replicate 1 but not in replicate 2. Estimates of the genetic correlation between weight gain from 5 to 9 weeks of age and percent mortality under heat stress after two generations of selection in replicate 2 was -.004, and after three generations of selection in replicate 1 was +.076.

Response to selection at two temperatures for fast and slow growth from five to nine weeks of age in poultry.

Cornell Control White Leghorn chicks were grown in a common environment to five weeks of age and selected for fast and slow gain in body weight from five to nine weeks of age at two temperatures, 21.1 degrees (cold) and 32.2 degrees (hot), during which time a constant 50% relative humidity was maintained. All lines were tested each generation in both temperature environments. Selection continued for four generations, with a second replicate started six weeks after the first replicate in each generation. In the hot environment, a 20% reduction (104 g) in five-to-nine-week weight gain was found. The responses to selection for fast and slow growth were symmetrical except in the first generation, when an outbreak of bronchitis confounded selection for body weight with selection for disease resistance and allowed little gain in the slow lines. No genotype-by-environment interactions were found, indicating that selection in either direction in either selection temperature produced equal responses in either test temperature. This suggests that any interactions observed between the growth of strains in tropical vs. temperature climates must be due to some difference between these environments other than the temperature differences studied.

Synthesis and biological activity of 5-(4-chlorobenzoyl)-4-(hydroxymethyl)-1-methyl-1H-pyrrole-2-acetic acid, a major metabolite of zomepirac sodium.

5-(4-Chlorobenzoyl)-4-(hydroxymethyl)-1-methyl-1H-pyrrole-2-acetic acid (2), the major oxidative metabolite of zomepirac (1), was synthesized starting with ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate (3), the ethyl ester of 1. Compound 3 was oxidized with selenium dioxide to afford the alpha-oxoester, 5. Bromination of 5 with N-bromosuccinimide produced bromomethylpyrrole 7, and reaction of 7 with acetate produced by corresponding acetoxymethylpyrrole 8. Hydrogen sulfide effected the selective reduction of the side-chain carbonyl group if 8 to give 9. Saponification of 9 gave the title compound, 2. Synthetic 2 was identical with the isolated metabolite of zomepirac (1). Biological testing revealed that the metabolite was essentially devoid of the biological activity associated with zomepirac.

New library buildings. Part VI: Sciences Library, Brown University.

Brown was one of the first universities in the nation to combine its science collections into a single library in the interest of aiding interdisciplinary teaching and research. This paper discusses the evolution of the Sciences Library and its resources, the development of the medical education program, and the physical aspects of the new library building. A fifteen-story tower, housing the collections of the physical, biological, and medical sciences, symbolizes the interdisciplinary approach to teaching and research at Brown University.