Microstructural view of burrowing with a bioinspired digging robot.

RoboClam is a burrowing technology inspired by Ensis directus, the Atlantic razor clam. Atlantic razor clams should only be strong enough to dig a few centimeters into the soil, yet they burrow to over 70 cm. The animal uses a clever trick to achieve this: by contracting its body, it agitates and locally fluidizes the soil, reducing the drag and energetic cost of burrowing. RoboClam technology, which is based on the digging mechanics of razor clams, may be valuable for subsea applications that could benefit from efficient burrowing, such as anchoring, mine detonation, and cable laying. We directly visualize the movement of soil grains during the contraction of RoboClam, using a novel index-matching technique along with particle tracking. We show that the size of the failure zone around contracting RoboClam can be theoretically predicted from the substrate and pore fluid properties, provided that the timescale of contraction is sufficiently large. We also show that the nonaffine motions of the grains are a small fraction of the motion within the fluidized zone, affirming the relevance of a continuum model for this system, even though the grain size is comparable to the size of RoboClam.

Razor clam to RoboClam: burrowing drag reduction mechanisms and their robotic adaptation.

Estimates based on the strength, size, and shape of the Atlantic razor clam (Ensis directus) indicate that the animal's burrow depth should be physically limited to a few centimeters; yet razor clams can dig as deep as 70 cm. By measuring soil deformations around burrowing E. directus, we have found the animal reduces drag by contracting its valves to initially fail, and then fluidize, the surrounding substrate. The characteristic contraction time to achieve fluidization can be calculated directly from soil properties. The geometry of the fluidized zone is dictated by two commonly-measured geotechnical parameters: coefficient of lateral earth pressure and friction angle. Calculations using full ranges for both parameters indicate that the fluidized zone is a local effect, occurring between 1-5 body radii away from the animal. The energy associated with motion through fluidized substrate-characterized by a depth-independent density and viscosity-scales linearly with depth. In contrast, moving through static soil requires energy that scales with depth squared. For E. directus, this translates to a 10X reduction in the energy required to reach observed burrow depths. For engineers, localized fluidization offers a mechanically simple and purely kinematic method to dramatically reduce energy costs associated with digging. This concept is demonstrated with RoboClam, an E. directus-inspired robot. Using a genetic algorithm to find optimal digging kinematics, RoboClam has achieved localized fluidization burrowing performance comparable to that of the animal, with a linear energy-depth relationship, in both idealized granular glass beads and E. directus' native cohesive mudflat habitat.

Benzofuro[3,2-b]pyridines as mixed ET(A)/ET(B) and selective ET(B) endothelin receptor antagonists.

The discovery, synthesis and structure-activity relationships of a series of novel benzofuro[3,2-b]pyridines as non-selective endothelin ET(A)/ET(B) as well as selective ET(B) receptor antagonists are described. The most potent non-selective inhibitor 7s displayed an IC50 of 21 nM and 41 nM for ET(A) and ET(B) receptors, respectively, whereas 7ee merely showed affinity for the ET(B) receptor (IC50 = 3.6 nM).

Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist.

The discovery, in vitro and in vivo studies of the highly potent ETA antagonist EMD 122946 are presented. This compound displayed high binding affinity and functional antagonism [IC50 = 3.2 x 10(-11) M, pA2 = 9.5 (ETA)] and inhibited the ET-1 induced pressor response in pithed rats with an ED50 of 0.3 mg/kg. In conscious spontaneously hypertensive rats and in DOCA-salt hypertensive rats the compound lowered mean blood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bioavailability in rats and monkeys.

Endothelin antagonists: search for surrogates of methylendioxyphenyl by means of a Kohonen neural network.

The methylendioxyphenyl group, present in a number of potent endothelin receptor antagonists, could have undesirable metabolic interactions with cytochrome P450 in vivo. Using a self-organizing neural network we analysed the features of molecular electrostatic potentials of several endothelin receptor ligands. A library of small "fragments and functional groups" together with their corresponding Kohonen maps was generated. By means of this Kohonen map library we discovered the benzothiadiazole group as a surrogate for methylendioxyphenyl.

Endothelin antagonists: evaluation of 2,1,3-benzothiadiazole as a methylendioxyphenyl bioisoster.

The methylendioxyphenyl group is present in a number of endothelin receptor antagonists thus far reported. By means of a Kohonen neural network we discovered with a benzothiadiazole a bioisosteric replacement instead. This group should be devoid of the negative metabolic interactions with cytochrome P450 ascribed to methylendioxyphenyl in vivo. The synthesis of a potent benzothiadiazole analogue EMD 122801 together with in vitro studies of different methylendioxyphenyl, benzothiadiazole and benzofurazan derivatives is described.

Non-peptide angiotensin II receptor antagonists: synthesis and biological activity of a series of novel 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine derivatives.

A series of novel non-peptide angiotensin II receptor antagonists containing a 2,3,5-trisubstituted 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine was prepared via several synthetic routes. Their affinity for angiotensin II receptors was established in a binding assay experiment and in an isolated-organ test. Molecules with small alkyl groups at C-2 and the (methylbiphenylyl)tetrazole moiety at N-3 were the preferred compounds with affinities and potencies in the nanomolar range. Variations at the N-5 position modulate the activity. Substitution at N-5 with various benzyl groups led to derivatives with in vitro potencies in the nanomolar range, which were equivalent to those of losartan in these assays. Replacement of the N-5 hydrogen with acetic acid esters or, in particular, acetamides gave molecules with increased activity. The most potent was 2-butyl-4,5-dihydro-4-oxo-3-[[2'-(1H-tetrazol-5-yl)-4- biphenylyl]methyl]-3H-imidazo[4,5-c]pyridine-5- (N,N-diethylacetamide) (14u), which is superior to L-158,809 in vitro. Two prototypes were selected as their potassium salts for in vivo testing as antihypertensives. Compounds 14a (EMD 61,650) and 14q (EMD 66,684) reduced blood pressure dose dependently in spontaneously hypertensive rats when administered iv. In this assay, acetamide 14q is superior to losartan.